count source_label source_id relationship target_label target_id entity_type solr_id publication_id sentences 16 Chlorzoxazone MESH:D002753 activates UNIPROT:Q13422 Protein 7878b4c2-297c-11e6-b4a6-001a4ae51246 10.1074/jbc.275.1.585 Also, we recently demonstrated that the cloned hIK1 is directly activated by 1-ethyl-2-benzimidazolinone and chlorzoxazone in a Ca2+dependent manner (36), similar to our previous reports on the endogenous channel (16,37). 16 CHEBI:34076 activates Chlorzoxazone MESH:D002753 Chemical 7878b4c2-297c-11e6-b4a6-001a4ae51246 10.1074/jbc.275.1.585 Also, we recently demonstrated that the cloned hIK1 is directly activated by 1-ethyl-2-benzimidazolinone and chlorzoxazone in a Ca2+dependent manner (36), similar to our previous reports on the endogenous channel (16,37). 10 Chlorzoxazone MESH:D002753 hydroxylatesProtein UNIPROT:P05181 Protein bd59488c-3946-11e8-8f56-001a4a160175 15135088 Chlorpromazine, desipramine and fluphenazine at a concentration of 1mM were capable of inhibiting chlorzoxazone 6-hydroxylation of CYP2E1 only to a little extent (by about 50–60%), whereas thioridazine caused minor inhibition of CYP2E1 (Fig. 3).|||On the other hand, diclofenac did not affect chlorzoxazone 6-hydroxylation of CYP2E1, while the activities of CYP2A6 and CYP2C19 were reduced marginally at a concentration of 1mM (Fig. 4).|||Finally, it should be emphasized that clotrimazole exhibited a weak inhibitory effect on chlorzoxazone 6-hydroxylation of CYP2E1 at a concentration of 250μM. 10 Chlorzoxazone MESH:D002753 activates CHEBI:29103 Chemical 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 Chlorzoxazone, a centrally acting muscle relaxant (Kaneko et al., 1989), activates intermediate-conductance, Ca2+-activated K+channels in aortic endothelial cells (Ahn et al., 2004) and cloned intermediate-conductance, Ca2+-activated K+channels (Syme et al., 2000).|||In neuroblastoma IMR-32 cells, chlorzoxazone also stimulated large-conductance Ca2+-activated K+channel activity (Liu et al., 2003).|||Since large-conductance Ca2+-activated K+channels are present in artery smooth muscle cells but not endothelial cells (Mistry and Garland, 1998; Walker et al., 2001), we speculate the chlorzoxazone-induced relaxation is due to the activation of large-conductance Ca2+-activated K+channels in the smooth muscle cells.|||It has been reported that chlorzoxazone activates large-conductance Ca2+-activated K+channels (Liu et al., 2003).|||Because chlorzoxazone is widely used as a tool to demonstrate the role of intermediate-conductance, Ca2+-activated K+channels in studies of vascular function, it is important to characterize the chlorzoxazone-induced relaxation and test whether the drug is a specific opener of intermediate-conductance Ca2+-activated K+channels. 8 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P35228 Protein b663a5e0-9c35-11e6-b002-001a4ae51247 10.1074/jbc.272.2.977 "The addition of chlorzoxazone then reversed the type II imidazole-induced spectra of iNOS, to give a type I difference spectra (λmaxat 394 nm and λminat 432 nm) (Fig. 4).|||The mechanism of inhibition of iNOS by chlorzoxazone was examined as well as the binding of chlorzoxazone to human and rat hepatic microsomal P-450s.|||Inhibition of iNOS by Chlorzoxazone Chlorzoxazone was titrated against 1 μML-Arg and inhibited iNOSL-citrulline production with an IC50value of 6.9 ± 1.8 μM.|||Reversible Type I Binding of Chlorzoxazone to iNOS Because the inhibition of iNOS by chlorzoxazone is competitive with respect toL-Arg, chlorzoxazone is most likely binding within the heme domain.|||The inhibition of iNOS by chlorzoxazone was competitive with respect toL-Arg withKi= 3.3 ± 0.7 μM(Fig. 2).|||Whereas the inhibition of iNOS by chlorzoxazone suggests that iNOS may have similar substrate affinity as CYP2E1 (or cytochrome P-450 1A1), it is unlikely because none of the other CYP2E1 (or cytochrome P-450 1A1) selective compounds were inhibitors of iNOS.|||The results presented here demonstrate that chlorzoxazone is a potent inhibitor of iNOS and to our knowledge is the first report of a benzoxazole class of NOS inhibitor." 8 Chlorzoxazone MESH:D002753 activates UNIPROT:P00918 Protein 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 Because chlorzoxazone is widely used as a tool to demonstrate the role of intermediate-conductance, Ca2+-activated K+channels in studies of vascular function, it is important to characterize the chlorzoxazone-induced relaxation and test whether the drug is a specific opener of intermediate-conductance Ca2+-activated K+channels.|||Moreover,Cao et al., 2001have reported that chlorzoxazone activates small-conductance Ca2+-activated K+channels (rSK2 channels expressed in HEK293 mammalian cells).|||Chlorzoxazone, a centrally acting muscle relaxant (Kaneko et al., 1989), activates intermediate-conductance, Ca2+-activated K+channels in aortic endothelial cells (Ahn et al., 2004) and cloned intermediate-conductance, Ca2+-activated K+channels (Syme et al., 2000).|||It has been reported that chlorzoxazone activates large-conductance Ca2+-activated K+channels (Liu et al., 2003). 8 UNIPROT:P00918 activates Chlorzoxazone MESH:D002753 Protein 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 In contrast, the non-selective Ca2+-activated K+channel blocker, tetraethylammonium, the large-conductance Ca2+-activated K+channel blocker, ethanol (Dopico, 2003; Liu et al., 2004) and paxilline (Chanrachakul et al., 2004; Benhassine and Berger, 2005), significantly antagonized the chlorzoxazone-induced relaxation.|||5, the chlorzoxazone-induced relaxation of the endothelium-intact artery pre-contracted by noradrenaline was antagonized by 75 mM ethanol and 2 μM paxilline, indicating that chlorzoxazone-induced relaxation by activation of large-conductance, Ca2+-activated K+channels. 8 MESH:D012451 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype c1136a24-bc03-11e5-9b9d-001a4ae51247 10.1016/j.fct.2005.01.008 The addition of 50μM safrole caused 71%, 86%, 36%, and 87% decreases of 7-ethoxyresorufinO-deethylation, coumarin hydroxylation, dextromethorphanO-demethylation, and chlorzoxazone hydroxylation activities, respectively (Table 2).|||In human liver microsomes, safrole at 50μM caused more than 70% loss of 7-ethoxyresorufinO-deethylation, coumarin hydroxylation and chlorzoxazone hydroxylation activities (Table 2). 6 Chlorzoxazone MESH:D002753 activates UNIPROT:P13569 Protein d43eee5e-bc47-11e5-ac4e-001a4ae51246 10.1016/j.resp.2007.03.016 Effect of CFTRinh-172 on chlorzoxazone induced currents Finally, we used the highly selective inhibitor CFTRinh-172 (Ma et al., 2002) in combination with the putative CFTR activator chlorzoxazone (Singh et al., 2000).|||Here, we present evidence concerning a luminal Cl−secretion in this tissue, which was sensitive to common CFTR inhibitors (NPPB, NFA, glibenclamide, lonidamine and CFTRinh-172;Schultz et al., 1999; Ma et al., 2002) and could be augmented by the CFTR activator chlorzoxazone (Singh et al., 2000; Cuthbert, 2001).|||Finally, we used the highly selective inhibitor CFTRinh-172 (Ma et al., 2002) in combination with the putative CFTR activator chlorzoxazone (Singh et al., 2000). 6 CHEBI:29103 activates Chlorzoxazone MESH:D002753 Chemical 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 5, the chlorzoxazone-induced relaxation of the endothelium-intact artery pre-contracted by noradrenaline was antagonized by 75 mM ethanol and 2 μM paxilline, indicating that chlorzoxazone-induced relaxation by activation of large-conductance, Ca2+-activated K+channels.|||In contrast, the non-selective Ca2+-activated K+channel blocker, tetraethylammonium, the large-conductance Ca2+-activated K+channel blocker, ethanol (Dopico, 2003; Liu et al., 2004) and paxilline (Chanrachakul et al., 2004; Benhassine and Berger, 2005), significantly antagonized the chlorzoxazone-induced relaxation. 6 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 885d82f4-bc4a-11e5-8d2d-001a4ae51247 10.1016/j.ejphar.2007.06.032 Interestingly,Kobayashi et al. (2002)reported that the hydroxylation of chlorzoxazone was catalyzed mainly by CYP2E1, but also to a lesser extent by CYP3A and CYP1A in rat cDNA-expression systems.|||However,Jayyosi et al. (1995)reported that only CYP2E1 and CYP3A, but not CYP1A, are major contributors to chlorzoxazone hydroxylation in hepatic microsomes of normal rats, based on an immunoinhibition study.|||However,Amato et al. (1998)reported that p-nitrophenol and chlorzoxazone seemed more specific than aniline for mammalian CYP2E1.Kobayashi et al. (2002)confirmed thatp-nitrophenol and chlorzoxazone are mainly hydroxylated by CYP2E1, and to a lesser extent by cytochrome P4503A (CYP3A) and cytochrome P4501A (CYP1A) family members. 5 Chlorzoxazone MESH:D002753 activates UNIPROT:Q9H2S1 Protein a6cbe050-cb27-11e5-b419-001a4ae51246 11181893 "Moreover, NS 1619 also inhibited the rSK2 channel currents activated by chlorzoxazone, 1-EBIO, and zoxazolamine.|||Instead, this compound inhibited rSK2 channel currents activated by either chlorzoxazone, 1-EBIO, zoxazolamine, or elevated intracellular Ca2+.|||In conclusion, we have shown that chlorzoxazone, 1-EBIO, and zoxazolamine activate recombinant rat brain SK2 channels in a Ca2+-independent manner.|||Chlorzoxazone, 1-EBIO, and zoxazolamine activated rSK2 channel currents in a concentration-dependent manner.|||First, chlorzoxazone and the structurally related compounds 1-EBIO and zoxazolamine activate recombinant rSK2 channels when applied extracellularly." 4 Chlorzoxazone MESH:D002753 dehydroxylatesProtein MESH:D004008 Phenotype 26c26cf0-3955-11e8-8636-001a4a160175 10449188 Chlorzoxazone, a specific substrate for CYP2E1[26], caused no inhibition of diclofenac hydroxylation. 4 Chlorzoxazone MESH:D002753 activates UNIPROT:P00918 Protein be6f65a8-5cb0-11e7-8c5f-001a4ae51246 PMC4778569 Feeding mice the FDA-approved muscle relaxant chlorzoxazone (CHZ) increases the probability of opening Ca2+-dependent K+channels, which affects firing and improves motor performance in ataxic mice (Alvina and Khodakhah, 2010; Gao et al., 2012).|||Chlorzoxazone corrects several properties of Purkinje cell firing inCar8wdlmice Feeding mice the FDA-approved muscle relaxant chlorzoxazone (CHZ) increases the probability of opening Ca2+-dependent K+channels, which affects firing and improves motor performance in ataxic mice (Alvina and Khodakhah, 2010; Gao et al., 2012). 4 MESH:D000431 hydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype 2b5de5c6-bc40-11e5-8abe-001a4ae51246 10.1016/j.freeradbiomed.2003.09.007 For example, hydroxylation of chlorzoxazone, testosterone 7α, 16β, ω, and ω-1 lauric acid were all increased by chronic alcohol in both species. 4 MESH:D004464 inhibits Chlorzoxazone MESH:D002753 Phenotype bd59488c-3946-11e8-8f56-001a4a160175 15135088 Bifonazole and econazole were able to reduce both chlorzoxazone andp-nitrophenol hydroxylase activities, whereas the other three antifungals had no effects on this activity (Table 4). 4 UNIPROT:Q969K3 activates Chlorzoxazone MESH:D002753 Protein 2aa74fbc-3409-11e8-9192-001a4a160175 25835148 Hepatic microsomal chlorzoxazone hydroxylase activity was significantly increased by RIF in normal mice. 4 CHEBI:31286 inhibits Chlorzoxazone MESH:D002753 Chemical bd59488c-3946-11e8-8f56-001a4a160175 15135088 Bifonazole and econazole were able to reduce both chlorzoxazone andp-nitrophenol hydroxylase activities, whereas the other three antifungals had no effects on this activity (Table 4). 4 CHEBI:26020 activates Chlorzoxazone MESH:D002753 Chemical 6b407bbc-0d1d-11f0-b40b-0050569a1f61 10.1016/S0014-5793(99)01361-7 The incubation mixture consisted of 100 μg sonically disrupted mitochondria, 50 μM chlorzoxazone, a NADPH generating system (0.2 mM NADPH, 2.0 mM glucose 6-phosphate and 3 U/ml glucose 6-phosphate dehydrogenase), 1 nmol adrenodoxin (Adx), 0.1 nmol adrenodoxin reductase (AdR), kindly supplied by Prof. Rita Bernhardt, University of Saarbrücken, Germany, and 50 mM phosphate buffer pH 7.4 in a final volume of 0.25 ml. 4 UNIPROT:P08684 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 669b4cf0-1df7-11f0-b759-0050569a791b 10.1124/dmd.122.001198 CYP1A2-mediated phenacetinO-deethylation, CYP2B6-mediated bupropion 4-hydroxylation, CYP2C8-mediated amodiaquineN-deethylation, CYP2C9-mediated diclofenac 4′-hydroxylation, CYP2C19-mediated mephenytoin 4′-hydroxylation, CYP2D6-mediated bufuralol 1′-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated midazolam 1′-hydroxylation were measured using a typical incubation mixture (at a final volume of 0.2 ml) consisting of substrate, enzyme sources, buffer, and a reduced NADP (NADPH)-generating system (0.5 mM NADP+, 5 mM glucose 6-phosphate, and 0.5 unit/ml glucose 6-phosphate dehydrogenase). 4 MESH:D051379 activates Chlorzoxazone MESH:D002753 Phenotype 2aa74fbc-3409-11e8-9192-001a4a160175 25835148 Hepatic microsomal chlorzoxazone hydroxylase activity was significantly increased by RIF in normal mice. 4 CHEBI:53329 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Chemical 2b5de5c6-bc40-11e5-8abe-001a4ae51246 10.1016/j.freeradbiomed.2003.09.007 ABT treatment caused a significant decrease in CYP-associated activities in animals fed high-fat control diet, particularly the hydroxylation of chlorzoxazone, ω and ω-1 lauric acid, and testosterone 6β and 16α. 4 CHEBI:53329 inhibits Chlorzoxazone MESH:D002753 Chemical 2b5de5c6-bc40-11e5-8abe-001a4ae51246 10.1016/j.freeradbiomed.2003.09.007 For example, ABT inhibited chlorzoxazone catalytic activity to below basal values, independent of alcohol administration in both species. 4 UNIPROT:P05177 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 669b4cf0-1df7-11f0-b759-0050569a791b 10.1124/dmd.122.001198 CYP1A2-mediated phenacetinO-deethylation, CYP2B6-mediated bupropion 4-hydroxylation, CYP2C8-mediated amodiaquineN-deethylation, CYP2C9-mediated diclofenac 4′-hydroxylation, CYP2C19-mediated mephenytoin 4′-hydroxylation, CYP2D6-mediated bufuralol 1′-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated midazolam 1′-hydroxylation were measured using a typical incubation mixture (at a final volume of 0.2 ml) consisting of substrate, enzyme sources, buffer, and a reduced NADP (NADPH)-generating system (0.5 mM NADP+, 5 mM glucose 6-phosphate, and 0.5 unit/ml glucose 6-phosphate dehydrogenase). 4 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 2aa74fbc-3409-11e8-9192-001a4a160175 25835148 Chlorzoxazone hydroxylation to 6-hydroxy chlorzoxazone is mediated by the CYP2E1 isoform (Lee and Kim, 2013). 4 UNIPROT:Q92039 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 885d82f4-bc4a-11e5-8d2d-001a4ae51247 10.1016/j.ejphar.2007.06.032 However,Jayyosi et al. (1995)reported that only CYP2E1 and CYP3A, but not CYP1A, are major contributors to chlorzoxazone hydroxylation in hepatic microsomes of normal rats, based on an immunoinhibition study.|||Interestingly,Kobayashi et al. (2002)reported that the hydroxylation of chlorzoxazone was catalyzed mainly by CYP2E1, but also to a lesser extent by CYP3A and CYP1A in rat cDNA-expression systems. 4 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein 68070126-3748-11e8-9fbf-001a4a160176 26947455 In vitrodetermination of CYP2E1 activity CYP2E1 activity was determined by CYP2E1-mediated chlorzoxazone 6-hydroxylation in the liver microsome system described previously[24,25].|||CYP2E1 activity was determined by CYP2E1-mediated chlorzoxazone 6-hydroxylation in the liver microsome system described previously[24,25]. 3 Chlorzoxazone MESH:D002753 inhibits MESH:D000431 Phenotype 1c63f752-bc01-11e5-9b9d-001a4ae51247 PMC3062269 Chlorzoxazone significantly and dose-dependently reduced alcohol drinking in IAA rats, determined after 3 hours access to alcohol (Figure 2A)[F(3,74) = 17.45,p< .001] or 1 hour access to alcohol (Figure 2C) [F(3,74) = 20.63,p< .001]. 3 UNIPROT:Q969K3 inhibits Chlorzoxazone MESH:D002753 Protein 2aa74fbc-3409-11e8-9192-001a4a160175 25835148 Chemicals and reagents RIF, glycerol, sodium dithionite (sodium hydrosulfite), NADH, reduced NADPH, cytochrome c, resorufin, ethoxyresorufin, methoxyresorufin, pentoxyresorufin, tolbutamide, 4-hydroxytolbutamide, chlorzoxazone, 6-hydroxychlorzoxazone, carbamazepine, saccharo-1,4-lactone, alamethicin, magnesium chloride, β-estradiol, chenodeoxycholic acid, serotonin, mefenamic acid, and uridine 5′-diphosphoglucuronic acid (UDPGA) were purchased from Sigma–Aldrich (St. Louis, MO).|||Materials and methods RIF, glycerol, sodium dithionite (sodium hydrosulfite), NADH, reduced NADPH, cytochrome c, resorufin, ethoxyresorufin, methoxyresorufin, pentoxyresorufin, tolbutamide, 4-hydroxytolbutamide, chlorzoxazone, 6-hydroxychlorzoxazone, carbamazepine, saccharo-1,4-lactone, alamethicin, magnesium chloride, β-estradiol, chenodeoxycholic acid, serotonin, mefenamic acid, and uridine 5′-diphosphoglucuronic acid (UDPGA) were purchased from Sigma–Aldrich (St. Louis, MO). 2 Chlorzoxazone MESH:D002753 activates UNIPROT:O94907 Protein 9aa77a3c-bc4a-11e5-9b9d-001a4ae51247 10.1016/S0014-2999(02)01987-8 Third, riluzole has some structural similarity to compounds such as chlorzoxazone, 1-EBIO, and zoxazolamine that modulate native and recombinant SK channels(Cao et al., 2001; Pedarzani et al., 2001). 2 Chlorzoxazone MESH:D002753 activates UNIPROT:Q9H2S1 Protein 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 Moreover,Cao et al., 2001have reported that chlorzoxazone activates small-conductance Ca2+-activated K+channels (rSK2 channels expressed in HEK293 mammalian cells). 2 Chlorzoxazone MESH:D002753 activates CHEBI:28483 Chemical 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 It has been suggested that intermediate-conductance, Ca2+-activated K+channels are responsible for mediating hyperpolarization of endothelial cells (Eichler et al., 2003) and for the chlorzoxazone-induced relaxation of mouse aortic artery (Ahn et al., 2004). 2 Chlorzoxazone MESH:D002753 activates MESH:D000431 Phenotype 5f644aba-3554-11e8-8636-001a4a160175 10614722 As shown inTable 3, ethanol cytotoxicity was also prevented by inhibitors of alcohol dehydrogenase (methylpyrazole or dimethylsulfoxide), or aldehyde dehydrogenase (disulfiram, chloral hydrate, cyanamide, pargyline) or CYP2E1 (chlorzoxazone, cimetidine, phenylimidazole, benzylimidazole, aminotriazole) but not by inhibitors of other cytochrome P450s (metyrapone, SKF-525A). 2 Chlorzoxazone MESH:D002753 inhibits MESH:D020058 Phenotype ea5dac16-3391-11e8-8636-001a4a160175 11551533 Both chlorzoxazone (CYP2E1) and 5-phenyl-1-pentyne (CYP2F2) reduced the rate of metabolism of styrene in rat and mouse nasal microsomal fractions, but by far the most efficient was 5-phenyl-1-pentyne (Fig. 1). 2 Chlorzoxazone MESH:D002753 inhibits GO:0008152 Phenotype ea5dac16-3391-11e8-8636-001a4a160175 11551533 Both chlorzoxazone (CYP2E1) and 5-phenyl-1-pentyne (CYP2F2) reduced the rate of metabolism of styrene in rat and mouse nasal microsomal fractions, but by far the most efficient was 5-phenyl-1-pentyne (Fig. 1). 2 Chlorzoxazone MESH:D002753 activates CHEBI:29103 Chemical e853d220-cb28-11e5-8189-001a4ae51246 11404241 Chlorzoxazone increases the basolateral K+permeability in CFT1 cells (data not shown), which causes the membrane potential to hyperpolarize.|||Addition of the basolateral K+channel activator chlorzoxazone accelerates the K+recycling, therefore providing a driving force for Cl−secretion into the apical fluid. 2 Chlorzoxazone MESH:D002753 inhibits GO:0008152 Phenotype f81b906c-cbf0-11e5-83a8-001a4ae51246 10473105 "α-Naphthoflavone, quercetin, chlorzoxazone, and phenacetin-inhibited CYP1A1- and CYP1A2-catalyzed DTIC metabolism.|||α-Naphthoflavone, quercetin, phenacetin, and chlorzoxazone were also potent inhibitors of DTIC metabolism by three other liver microsome preparations (data not shown)." 2 Chlorzoxazone MESH:D002753 activates MESH:D006851 Phenotype 3022dd64-c47e-11e5-91a7-001a4ae51247 20410470 The application of chlorzoxazone (500 μM, basolateral) led to a significant increase of the ISC, indicating an increased Cl−secretion (Fig. 3A).|||Chlorzoxazone was used to induce Cl−secretion, since it has been described as a secretagogue (6,38). 2 MESH:D000431 activates Chlorzoxazone MESH:D002753 Phenotype 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 In contrast, the non-selective Ca2+-activated K+channel blocker, tetraethylammonium, the large-conductance Ca2+-activated K+channel blocker, ethanol (Dopico, 2003; Liu et al., 2004) and paxilline (Chanrachakul et al., 2004; Benhassine and Berger, 2005), significantly antagonized the chlorzoxazone-induced relaxation. 2 MESH:D019789 activates Chlorzoxazone MESH:D002753 Phenotype 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 In contrast, the non-selective Ca2+-activated K+channel blocker, tetraethylammonium, the large-conductance Ca2+-activated K+channel blocker, ethanol (Dopico, 2003; Liu et al., 2004) and paxilline (Chanrachakul et al., 2004; Benhassine and Berger, 2005), significantly antagonized the chlorzoxazone-induced relaxation. 2 MESH:D008825 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype bd59488c-3946-11e8-8f56-001a4a160175 15135088 In contrast to the results of Tassaneeyakul et al.[12], miconazole was not able to decrease effectivelyp-nitrophenol or chlorzoxazone hydroxylation. 2 FPLX:CYP hydroxylatesProtein Chlorzoxazone MESH:D002753 ProteinFamily 7c487c02-f130-11ee-b346-0050569a791b 10.1016/S0300-483X(03)00026-X One possible explanation is that in the rat other cytochrome P450 proteins may be able to support the 6-hydroxylation of chlorzoxazone. 2 FPLX:CYP hydroxylatesProtein Chlorzoxazone MESH:D002753 ProteinFamily 64adc226-3388-11e8-bf76-001a4a160175 27105555 Although several P450 isoforms could potentially participate in the 6-hydroxylation of chlorzoxazone, its strong inhibition by 4-methylpyrazole confirmed that P450 2E1 is the major isoform involved in these assay conditions. 2 UNIPROT:P13569 activates Chlorzoxazone MESH:D002753 Protein d43eee5e-bc47-11e5-ac4e-001a4ae51246 10.1016/j.resp.2007.03.016 This assumption is further supported by observations that a functional CFTR is required to activate chlorzoxazone induced transepithelial currents, since there was no chlorzoxazone effect detectable in DF508 human airway epithelia (Singh et al., 2000). 2 UNIPROT:P13569 inhibits Chlorzoxazone MESH:D002753 Protein d43eee5e-bc47-11e5-ac4e-001a4ae51246 10.1016/j.resp.2007.03.016 From these results we conclude that the observed increase inISCis due to an activation of a designated CFTR channel, especially since we were able to block almost the entire chlorzoxazone induced current with CFTRinh-172 (Fig. 4C). 2 MESH:D014535 inhibits Chlorzoxazone MESH:D002753 Phenotype 2aa74fbc-3409-11e8-9192-001a4a160175 25835148 Chemicals and reagents RIF, glycerol, sodium dithionite (sodium hydrosulfite), NADH, reduced NADPH, cytochrome c, resorufin, ethoxyresorufin, methoxyresorufin, pentoxyresorufin, tolbutamide, 4-hydroxytolbutamide, chlorzoxazone, 6-hydroxychlorzoxazone, carbamazepine, saccharo-1,4-lactone, alamethicin, magnesium chloride, β-estradiol, chenodeoxycholic acid, serotonin, mefenamic acid, and uridine 5′-diphosphoglucuronic acid (UDPGA) were purchased from Sigma–Aldrich (St. Louis, MO). 2 MESH:D009538 activates Chlorzoxazone MESH:D002753 Phenotype 694bd208-efcc-11ee-b346-0050569a791b 10.1016/j.bcp.2003.10.022 The results reported herein are consistent with recently reported research that shows that smoking inhibits nicotine metabolism[29], that smokers metabolize nicotine more slowly than do non-smokers[30]and that low doses of nicotine induce CYP2E1 and chlorzoxazone metabolism in rat liver[31]. 2 MESH:D002110 hydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype 14a4c50e-bc3e-11e5-ac4e-001a4ae51246 10.1016/S1090-0233(02)00174-0 Interestingly, the rate of thein vitro6-hydroxylation of chlorzoxazone, another model substrate, has been reported to be higher in equine hepatic microsomes than in preparations from other mammalian species including cows, pigs, dogs, and cats (Courtet al., 1997;Chauretet al., 1997). 2 UNIPROT:P08684 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 5b599fee-0cbe-11f0-b759-0050569a791b 10.1016/S0014-2999(00)00079-0 It has been reported that cDNA-expressed CYP3A4 and CYP1A2 are involved in the 6-hydroxylation of chlorzoxazone(Peter et al., 1990; Ono et al., 1995 Gorski et al., 1997)and, thus, both enzymes contained in liver microsomes may also be contributors of chlorzoxazone metabolism. 2 CHEBI:34907 activates Chlorzoxazone MESH:D002753 Chemical 73b8b148-bc4a-11e5-9b9d-001a4ae51247 10.1016/j.ejphar.2006.06.063 In contrast, the non-selective Ca2+-activated K+channel blocker, tetraethylammonium, the large-conductance Ca2+-activated K+channel blocker, ethanol (Dopico, 2003; Liu et al., 2004) and paxilline (Chanrachakul et al., 2004; Benhassine and Berger, 2005), significantly antagonized the chlorzoxazone-induced relaxation. 2 UNIPROT:P05177 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 5b599fee-0cbe-11f0-b759-0050569a791b 10.1016/S0014-2999(00)00079-0 It has been reported that cDNA-expressed CYP3A4 and CYP1A2 are involved in the 6-hydroxylation of chlorzoxazone(Peter et al., 1990; Ono et al., 1995 Gorski et al., 1997)and, thus, both enzymes contained in liver microsomes may also be contributors of chlorzoxazone metabolism. 2 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 7c487c02-f130-11ee-b346-0050569a791b 10.1016/S0300-483X(03)00026-X It is of interest that in bovine liver, CYP2E1 is responsible for the 6-hydroxylation of chlorzoxazone whereas in the dwarf goat it is catalysed by CYP1A (Court et al., 1997; Zweers-Zeilmaker et al., 1996). 2 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein 1f713108-bee5-11e5-bb7b-001a4ae51246 10.1016/j.toxlet.2005.11.015 Recently, fluconazole was shown to either have no inhibitory effect or minor inhibition of CYP 2C9-mediated tolbutamide hydroxylation, CYP2C19-mediatedS-mephenytoin 4′-hydroxylation, CYP3A4-mediated nifedipine oxidation, CYP1A2-mediated 7-ethoxyresorufmO-deethylation, CYP2D6-mediated debrisoquine 4-hydroxylation, or CYP2E1-mediated chlorzoxazone 6-hydroxylation activities in human liver microsomes (Niwa et al., 2005a,b). 2 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 1040cae4-0e2d-11f0-b40b-0050569a1f61 10.1016/S0022-2275(20)32545-1 Highly significant correlations were found between the (ω–1)-hydroxylation of oleic acid and the various CYP2E1-mediated monooxygenase enzyme activities, namely chlorzoxazone 6-hydroxylation, 4-nitrophenol hydroxylation, and lauric acid 11-hydroxylation, in a panel of 25 human liver microsomes. 2 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein ed640568-bee5-11e5-bb7b-001a4ae51246 10.1016/j.tiv.2006.07.008 Consistent with these findings, impaired antipyrine metabolism, which reflects total hepatic microsomal oxidative capacity, and a specific increase in CYP2E1-catalyzed chlorzoxazone metabolism were found in patients with NASH (Fiatarone et al., 1991; Pinto et al., 1996). 2 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein bce6df7c-bc4d-11e5-9b9d-001a4ae51247 10.1016/j.neuropharm.2005.11.001 Cigarette smoking accelerates chlorzoxazone metabolism in humans, most likely by induction of hepatic CYP2E1 activity (Benowitz et al., 2003). 2 UNIPROT:P05181 inhibits Chlorzoxazone MESH:D002753 Protein 5b599fee-0cbe-11f0-b759-0050569a791b 10.1016/S0014-2999(00)00079-0 The monoclonal antibody 1-73-18 for CYP2E1 inhibited the metabolism of chlorzoxazone,p-nitroanisole and toluene by 46%, 28% and 44%, respectively, with a large variability among individual livers, implying that other P450s except for CYP2E1 are also responsible for the residual activities in liver microsomes. 2 MESH:D012451 methylatesProtein Chlorzoxazone MESH:D002753 Phenotype c1136a24-bc03-11e5-9b9d-001a4ae51247 10.1016/j.fct.2005.01.008 The addition of 50μM safrole caused 71%, 86%, 36%, and 87% decreases of 7-ethoxyresorufinO-deethylation, coumarin hydroxylation, dextromethorphanO-demethylation, and chlorzoxazone hydroxylation activities, respectively (Table 2). 2 MESH:D010208 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype 0cad7b0a-cc26-11e5-85cd-001a4ae51247 9531516 "First, under conditions that would be expected to completely inhibit CYP1A2, papaverine (400 μM) inhibited the 6-hydroxylation of chlorzoxazone by only 15%, even at a substrate concentration of 3 μM (i.e.Km).|||In other words, papaverine inhibited the 6-hydroxylation of chlorzoxazone by 15% even in liver microsomes that contained negligible levels of CYP1A2, which suggests that the 15% inhibition observed represents weak inhibition of CYP2E1." 2 UNIPROT:P20711 inhibits Chlorzoxazone MESH:D002753 Protein 59c6a1e2-37aa-11e6-8a17-001a4ae51247 PMC4820800 The results showed that DDC inhibited chlorzoxazone metabolism in a dose-dependent manner (Figure 4B) in hepatic microsomes from caderofloxacin-treated and control rats.|||These results indicated that CYP2E1 is a major metabolic enzyme in chlorzoxazone depletion and chlorzoxazone metabolism could be inhibited by the CYP2E1 inhibitor DDC. 1 Chlorzoxazone MESH:D002753 activates UNIPROT:O15554 Protein a6cbe050-cb27-11e5-b419-001a4ae51246 11181893 "Our results confirm and extend a recent study showing that chlorzoxazone activates the structurally related IK channels encoded by the SK4 gene (Singh et al., 2000)." 1 Chlorzoxazone MESH:D002753 activates UNIPROT:O15554 Protein ea83a988-ae95-11ec-89b1-0050569a791b PMCPMC8746388 Chlorzoxazone also activates SK and IK channels, and 30 μM chlorzoxazone suppresses voltage-dependent L-type Ca currents [119]. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P20813 Protein 486ed3d8-ab95-11e6-9236-001a4ae51247 PMC4613945 Chlorzoxazone inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (midazolam and testosterone), and testosterone moderately inhibited CYP2B6 and CYP3A4/5 (midazolam) while weakly inhibiting CYP2C9. 1 Chlorzoxazone MESH:D002753 activates UNIPROT:P00918 Protein a6cbe050-cb27-11e5-b419-001a4ae51246 11181893 "In conclusion, we have shown that chlorzoxazone, 1-EBIO, and zoxazolamine activate recombinant rat brain SK2 channels in a Ca2+-independent manner." 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:O94907 Protein ea83a988-ae95-11ec-89b1-0050569a791b PMCPMC8746388 SK channels are also blocked by chlorzoxazone [187,188,189]. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:O94907 Protein f3bf649e-edce-11e5-9b35-001a4ae51246 PMC4762922 Previous work has suggested that chlorzoxazone reduces excitatory neurotransmission by modulating calcium-activated SK potassium channels [53]. 1 Chlorzoxazone MESH:D002753 activates UNIPROT:O94907 Protein ea83a988-ae95-11ec-89b1-0050569a791b PMCPMC8746388 Chlorzoxazone also activates SK and IK channels, and 30 μM chlorzoxazone suppresses voltage-dependent L-type Ca currents [119]. 1 Chlorzoxazone MESH:D002753 activates UNIPROT:O94907 Protein a6cbe050-cb27-11e5-b419-001a4ae51246 11181893 "Our results with rSK2 channels suggest that therapeutic concentrations of chlorzoxazone are likely to substantially activate SK channels in vivo." 1 Chlorzoxazone MESH:D002753 activates UNIPROT:O94907 Protein 1ece5680-bbf3-11e5-9b9d-001a4ae51247 PMC2847608 Our data are particularly exciting because the FDA-approved drug chlorzoxazone, which has been used for more than 30 years as a centrally acting myorelaxant (Chou et al., 2004), can activate SK channels in a similar manner as 1-EBIO (Cao et al., 2001). 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P11712 Protein 486ed3d8-ab95-11e6-9236-001a4ae51247 PMC4613945 Chlorzoxazone inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (midazolam and testosterone), and testosterone moderately inhibited CYP2B6 and CYP3A4/5 (midazolam) while weakly inhibiting CYP2C9. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P11509 Protein d3775bfe-cb8e-11e5-8106-001a4ae51247 11038157 "Ketoconazole (an inhibitor of CYP3A4) significantly inhibited amiodaroneN-deethylation to <10% of the control at 10 μM. Erythromycin (an inhibitor of CYP3A4) also inhibited it by ∼40% of the control at 100 μM. Coumarin (an inhibitor of CYP2A6), sulfaphenazole (an inhibitor of CYP2C9), and chlorzoxazone (an inhibitor of CYP2E1) had no effect on the amiodaroneN-deethylase activity at 100 μM." 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P11509 Protein 486ed3d8-ab95-11e6-9236-001a4ae51247 PMC4613945 Chlorzoxazone inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (midazolam and testosterone), and testosterone moderately inhibited CYP2B6 and CYP3A4/5 (midazolam) while weakly inhibiting CYP2C9. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P10632 Protein 486ed3d8-ab95-11e6-9236-001a4ae51247 PMC4613945 Chlorzoxazone inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (midazolam and testosterone), and testosterone moderately inhibited CYP2B6 and CYP3A4/5 (midazolam) while weakly inhibiting CYP2C9. 1 Chlorzoxazone MESH:D002753 activates UNIPROT:Q9H2S1 Protein 15177008-cb2b-11e5-b419-001a4ae51246 12237330 It has been reported that rSK2 and hIK are similarly activated by chlorzoxazone and related compound such as 1-ethyl-2-benzimidazolinon (1-EBIO) but that they are blocked selectively by apamin and clotrimazole, respectively (Jensen et al., 1998;Cao et al., 2001). 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P05177 Protein 486ed3d8-ab95-11e6-9236-001a4ae51247 PMC4613945 Chlorzoxazone inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (midazolam and testosterone), and testosterone moderately inhibited CYP2B6 and CYP3A4/5 (midazolam) while weakly inhibiting CYP2C9. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P05181 Protein d3775bfe-cb8e-11e5-8106-001a4ae51247 11038157 "Ketoconazole (an inhibitor of CYP3A4) significantly inhibited amiodaroneN-deethylation to <10% of the control at 10 μM. Erythromycin (an inhibitor of CYP3A4) also inhibited it by ∼40% of the control at 100 μM. Coumarin (an inhibitor of CYP2A6), sulfaphenazole (an inhibitor of CYP2C9), and chlorzoxazone (an inhibitor of CYP2E1) had no effect on the amiodaroneN-deethylase activity at 100 μM." 1 Chlorzoxazone MESH:D002753 activates UNIPROT:P05181 Protein c0deed00-c9fd-11e5-ab20-001a4ae51246 15123768 In other studies, mice were treated with DASO2and 5-phenyl-1-pentyne (5-PIP), both of which inhibit CYP2E1 and/or CYP2F2 (Chang et al., 1996;Roberts et al., 1998), and the inhibitory effects of these compounds on microsomal PNP and chlorzoxazone (CHZX) hydroxylase activities were determined. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P05181 Protein 1674ac80-5c12-11e7-9fde-001a4ae51247 PMC5438837 Therefore, the pharmacokinetic behaviors of chlorzoxazone indicate that FA inhibits rat hepatic CYP2E1 activity in vivo. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P05181 Protein c595a2a2-3950-11e8-9fbf-001a4a160176 19000661 CYP2E1 inhibitors phenylimidazole (PI) 300μM and chlorzoxazone (CLX) 50μM were each preincubated with hepatocytes for 30min to inhibit CYP2E1[29]. 1 Chlorzoxazone MESH:D002753 inhibits UNIPROT:P05181 Protein 5bf88126-c46c-11e5-91a7-001a4ae51247 PMC4049543 Rat CYP2E1 activity was inhibited by 500μM chlorzoxazone as reported previously (Howard et al., 2001). 1 Chlorzoxazone MESH:D002753 activates UNIPROT:P05181 Protein 7951250e-bc4a-11e5-8abe-001a4ae51246 10.1016/j.ejphar.2009.05.030 The alterations of chlorzoxazone (CZX) kinetics in infected mice, on the other hand, were consistent with malaria-induced downmodulation of CYP2E1 activity, because conversion of CZX into its primary metabolite 6-hydroxide chlorzoxazone (6OH-CZX) is catalyzed predominantly by this isoform. 1 Chlorzoxazone MESH:D002753 activates UNIPROT:Q8S905 Protein 15177008-cb2b-11e5-b419-001a4ae51246 12237330 It has been reported that rSK2 and hIK are similarly activated by chlorzoxazone and related compound such as 1-ethyl-2-benzimidazolinon (1-EBIO) but that they are blocked selectively by apamin and clotrimazole, respectively (Jensen et al., 1998;Cao et al., 2001). 1 Chlorzoxazone MESH:D002753 activates UNIPROT:P01042 Protein fd96bec0-75f9-11ee-add2-0050569a791b 10.1007/s12311-023-01584-8 Chlorzoxazone is an activator of both BK and SK KCN. 1 Chlorzoxazone MESH:D002753 inhibits CHEBI:84046 Chemical 2c3ff658-c471-11e5-91a7-001a4ae51247 PMC2687250 "This indicates that chlorzoxazone, at the concentration tested, is able to reduce pyoverdine production to a level resembling the level observed in QS deficiency." 1 Chlorzoxazone MESH:D002753 inhibits CHEBI:29108 Chemical ea83a988-ae95-11ec-89b1-0050569a791b PMCPMC8746388 Chlorzoxazone also activates SK and IK channels, and 30 μM chlorzoxazone suppresses voltage-dependent L-type Ca currents [119]. 1 Chlorzoxazone MESH:D002753 inhibits CHEBI:16974 Chemical 1c63f752-bc01-11e5-9b9d-001a4ae51247 PMC3062269 Chlorzoxazone significantly and dose-dependently reduced alcohol drinking in IAA rats, determined after 3 hours access to alcohol (Figure 2A)[F(3,74) = 17.45,p< .001] or 1 hour access to alcohol (Figure 2C) [F(3,74) = 20.63,p< .001]. 1 Chlorzoxazone MESH:D002753 activates MESH:D005978 Phenotype e853d220-cb28-11e5-8189-001a4ae51246 11404241 N-K4-M2GlyR (0.5 mM) plus chlorzoxazone increased GSH efflux ∼3.6-fold, which is comparable to the apical GSH content in CFTR-sufficient cells (CFT1-LCFSN). 1 Chlorzoxazone MESH:D002753 increases MESH:D005978 Phenotype e853d220-cb28-11e5-8189-001a4ae51246 11404241 However, chlorzoxazone (hyperpolarization) alone is not sufficient to cause any GSH secretion in the absence of Cl−secretion. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D006861 Phenotype c595a2a2-3950-11e8-9fbf-001a4a160176 19000661 Fructose cytotoxicity was also markedly increased by oxidative stress induced usingtert-butyl hydroperoxide instead of H2O2and was inhibited by aminobenzotriazole, a general suicide inhibitor for all cytochrome P450s or by chlorzoxazone, a specific CYP2E1 inhibitor. 1 Chlorzoxazone MESH:D002753 activates GO:0006810 Phenotype e853d220-cb28-11e5-8189-001a4ae51246 11404241 An earlier study (26) showed that chlorzoxazone stimulates transepithelial Cl−transport by activation of basolateral K+channels in normal airway epithelium but not in the nasal epithelium of CF patients, suggesting that apical Cl−-permeable pathways are necessary for the chlorzoxazone effect. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D001259 Phenotype fd96bec0-75f9-11ee-add2-0050569a791b 10.1007/s12311-023-01584-8 Chlorzoxazone improved balance and reduced the Scale for the Assessment and Rating of Ataxia score by 10% in a case of progressive cerebellar ataxia due to the heterozygous KCNMA1 point mutation G354S [24]. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D000431 Phenotype 1d983d4a-bc01-11e5-8abe-001a4ae51246 10.1016/j.biopsych.2011.02.007 Novel Targets for Nicotine and Alcohol Abuse Alcohol exposure alters SK-type potassium channel (SK) function in limbic brain regions.Hopfet al.(pages 618–624) show that chlorzoxazone, an FDA-approved activator of SK channels, reduces alcohol intake in rats exhibiting excessive intake but not in moderate-drinking rats. 1 Chlorzoxazone MESH:D002753 activates MESH:D000431 Phenotype 24a1a87c-bbd1-11e5-80fb-001a4ae51246 PMC3372087 Also the positive K channel modulator chlorzoxazone can inhibit firing in NAcb core neurons ex vivo and significantly and dose-dependently decrease alcohol intake in rats with intermittent access to alcohol compared to rats with continuous access to alcohol (Hopf et al., 2010, 2011a,b). 1 Chlorzoxazone MESH:D002753 inhibits MESH:D000431 Phenotype 1ece5680-bbf3-11e5-9b9d-001a4ae51247 PMC2847608 Still, this FDA-approved compound provides an unexpected and very exciting opportunity to design human clinical trials to examine whether chlorzoxazone reduces excessive or pathological alcohol drinking, and our study highlights the potential of SK channel activators as therapeutic agents against pathological alcohol consumption. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D000431 Phenotype af8362b6-bbfc-11e5-8abe-001a4ae51246 PMC3586202 Interestingly, chlorzoxazone, a US Food and Drug Administration (FDA)-approved positive modulator of Ca2+-activated K+channels (Cao, Dreixler, Roizen, Roberts, & Houamed, 2001; Liu, Lo, & Wu, 2003), reduces alcohol-seeking behavior in a rat model of CIE exposure (Hopf et al., 2011). 1 Chlorzoxazone MESH:D002753 inhibits MESH:D019789 Phenotype 7944d0ce-c8e8-11e5-a1fd-001a4ae51246 17916649 KCaexhibits an inwardly rectifying intermediate conductance (13); is activated by the benzimidazone derivatives 1-EBIO (10), DCEBIO (30), and chlorzoxazone (60); and is inhibited by charybdotoxin and tetraethylammonium (13). 1 Chlorzoxazone MESH:D002753 inhibits GO:0009058 Phenotype b663a5e0-9c35-11e6-b002-001a4ae51247 10.1074/jbc.272.2.977 At this blood concentration, chlorzoxazone might also inhibit NO biosynthesis. 1 Chlorzoxazone MESH:D002753 inhibits GO:0007268 Phenotype f3bf649e-edce-11e5-9b35-001a4ae51246 PMC4762922 Previous work has suggested that chlorzoxazone reduces excitatory neurotransmission by modulating calcium-activated SK potassium channels [53]. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D009569 Phenotype b663a5e0-9c35-11e6-b002-001a4ae51247 10.1074/jbc.272.2.977 At this blood concentration, chlorzoxazone might also inhibit NO biosynthesis. 1 Chlorzoxazone MESH:D002753 dehydroxylatesProtein MESH:D008874 Phenotype 3c4c7da6-c484-11e5-8491-001a4ae51247 PMC3654816 Earlier evidence based on in vivo CYP cocktail studies suggest that chlorzoxazone can significantly inhibit midazolam hydroxylation (CYP3A activity) in healthy human subjects[20]. 1 Chlorzoxazone MESH:D002753 inhibits GO:0008152 Phenotype 5bf88126-c46c-11e5-91a7-001a4ae51247 PMC4049543 In our hands, metabolism of 100μM PNP by liver microsomes from pyrazole-treated rats was inhibited by 73% with 500μM chlorzoxazone, a CYP2E1-sepcific inhibitor of rat CYP2E1. 1 Chlorzoxazone MESH:D002753 activates GO:0008152 Phenotype f81b906c-cbf0-11e5-83a8-001a4ae51246 10473105 "The most potent inhibitors of AIC formation were α-naphthoflavone, quercetin, phenacetin, chlorzoxazone, and disulfiram, which suggests CYP1A, CYP2E1, and CYP3A enzymes contributed to DTIC metabolism." 1 Chlorzoxazone MESH:D002753 activates MESH:D010455 Phenotype e853d220-cb28-11e5-8189-001a4ae51246 11404241 However, chlorzoxazone potentiated the effect of the peptide, causing, for instance, an increase in GSH release of 359 ± 16% of the control value with a concentration of N-K4-M2GlyR of 0.5 mM (P< 0.001). 1 Chlorzoxazone MESH:D002753 hydroxylatesProtein MESH:D051379 Phenotype 58892340-c9ff-11e5-b88f-001a4ae51247 15576447 "Usingp-nitrophenol as substrate to measure CYP2E1 activity, a greater level of inhibition was achieved with the anti-human CYP2E1 antibody compared with inhibition of chlorzoxazone 6-hydroxylation activity in theCYP2E1-humanized mice." 1 Chlorzoxazone MESH:D002753 activates MESH:D051379 Phenotype 0058dcbb-f587-11eb-93a5-001a4a160176 30610934 In the present study, EROD, PROD, and chlorzoxazone hydroxylation activities were elevated in smoking mice. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D051379 Phenotype 58892340-c9ff-11e5-b88f-001a4ae51247 15576447 "Using an inhibitory monoclonal antibody to human CYP2E1, chlorzoxazone 6-hydroxylation was reduced by approximately 30% in both wild-type andCYP2E1-humanized mice." 1 Chlorzoxazone MESH:D002753 activates MESH:D006851 Phenotype 0f8057c2-cb8f-11e5-a7a8-001a4ae51246 10913013 In support of this, recent data in normal volunteers indicate that chlorzoxazone, a skeletal muscle relaxant that is structurally related to 1-EBIO, and genistein, each stimulate Cl−secretion in human nasal epithelium (26,46). 1 Chlorzoxazone MESH:D002753 activates MESH:D006851 Phenotype 277fd5f0-c8ec-11e5-8b47-001a4ae51246 19060226 Conversely, it has been shown that KCa3.1 activation, by compounds such as 1-EBIO (49), DC-EBIO (75), 4-chlorobenzo[f]isoquinoline (CBIQ) (77), and chlorzoxazone (74), for example, stimulates Cl−secretion through CFTR and/or Ca2+-activated Cl−channels (CaCC) in non-CF airway cells. 1 Chlorzoxazone MESH:D002753 activates MESH:D006851 Phenotype e853d220-cb28-11e5-8189-001a4ae51246 11404241 An earlier study (26) showed that chlorzoxazone stimulates transepithelial Cl−transport by activation of basolateral K+channels in normal airway epithelium but not in the nasal epithelium of CF patients, suggesting that apical Cl−-permeable pathways are necessary for the chlorzoxazone effect. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D005632 Phenotype c595a2a2-3950-11e8-9fbf-001a4a160176 19000661 These fructose toxicity effects were found to be prevented by the P450 suicide general inhibitor aminobenzotriazole or the CYP2E1 inhibitors phenylimidazole and chlorzoxazone (Table 6). 1 Chlorzoxazone MESH:D002753 hydroxylatesProtein MESH:D013739 Phenotype 8e77b544-ca03-11e5-b88f-001a4ae51247 16204462 "Drug-Metabolizing Enzyme Activities.Four enzyme activities, namely, 7-ethoxyresorufinO-deethylation, 6β-hydroxylation of testosterone, tolbutamide 4-hydroxylation, and chlorzoxazone 6-hydroxylation, were analyzed in HepaRG cells cultured in five different experimental conditions (Table 5)." 1 Chlorzoxazone MESH:D002753 activates GO:0060081 Phenotype 15177008-cb2b-11e5-b419-001a4ae51246 12237330 The expression of SK2 and SK4 in HEK293 cells was confirmed by RT-PCR using subtype-specific primers and was verified functionally by membrane hyperpolarization induced by chlorzoxazone, which was then blocked by apamin and clotrimazole, respectively. 1 Chlorzoxazone MESH:D002753 hydroxylatesProtein MESH:D019782 Phenotype 2d32f300-cc76-11e5-aade-001a4ae51247 9316860 The CYP2E1 inhibitor chlorzoxazone also weakly inhibited riluzole N-hydroxylation (36% inhibition at 100 μM; IC50= 287 μM), but other inhibitors of this isoenzyme, such as aniline, isoniazid andp-nitrophenol, had minimal effect. 1 Chlorzoxazone MESH:D002753 inhibits MESH:D020820 Phenotype 4076eed2-c468-11e5-8491-001a4ae51247 PMC3653043 Application of EBIO or the clinically approved chlorzoxazone can regularize firing and reduce dyskinesia (Alviña and Khodakhah 2010;Walter et al. 2006). 1 Chlorzoxazone MESH:D002753 inhibits GO:0006919 Phenotype f3bf649e-edce-11e5-9b35-001a4ae51246 PMC4762922 Chlorzoxazone, copper sulphate, deferoxamine, felbinac, oligomycin and primidone all reduced caspase activation in a dose-dependent manner. 1 Chlorzoxazone MESH:D002753 activates FPLX:KCN ProteinFamily fd96bec0-75f9-11ee-add2-0050569a791b 10.1007/s12311-023-01584-8 Chlorzoxazone is an activator of both BK and SK KCN. 1 Chlorzoxazone MESH:D002753 inhibits FPLX:KCN ProteinFamily f3bf649e-edce-11e5-9b35-001a4ae51246 PMC4762922 Previous work has suggested that chlorzoxazone reduces excitatory neurotransmission by modulating calcium-activated SK potassium channels [53]. 1 Chlorzoxazone MESH:D002753 activates FPLX:KCN ProteinFamily f83c3702-bbea-11ee-9d3b-0050569a791b PMC6985344 The combination of the calcium-activated potassium channels activator chlorzoxazone (CHZ) and GABABagonist baclofen, that potentiates a subthreshold-activated potassium channel current, restored the spiking in SCA1 PCs and improved the dendritic hyperexcitability in SCA1-82Q mice and also sustained the improvement in the motor dysfunction in these mice [23]. 1 Chlorzoxazone MESH:D002753 inhibits FPLX:KCN ProteinFamily 766da8f8-390c-11e8-a51f-001a4a160176 27262624 Chlorzoxazone (Fig. 1) is a centrally acting muscle relaxant that decreases nerve firing rate by stimulating BKCatype potassium channels (Liu et al., 2003), and its effects on insects have not been investigated.N,N-diethylnicotinamide is an analog of DEET, a compound known to be repellent and toxic to mosquitoes, as well as a blocker of Kv2.1 type K+channels (Swale et al., 2014). 1 Chlorzoxazone MESH:D002753 activates FPLX:KCN ProteinFamily a556b610-ae96-11ec-b4ed-0050569a1f61 PMCPMC8309146 The potassium channel modulators chlorzoxazone and riluzole improved cerebellar electrophysiology in SCA2 patients, probably by modulating the excitability and dendritic plasticity of Purkinje cells [49,50,51]. 1 Chlorzoxazone MESH:D002753 inhibits FPLX:CYP ProteinFamily 486ed3d8-ab95-11e6-9236-001a4ae51247 PMC4613945 For example, because bupropion and chlorzoxazone strongly inhibited multiple P450 isoforms, 10 substrate mixtures containing varying concentrations (0.05Km, 0.1Km, 0.2Km, 0.4Km, and 0.8Km) of bupropion and chlorzoxazone were tested. 1 Chlorzoxazone MESH:D002753 inhibits FPLX:NOS ProteinFamily b663a5e0-9c35-11e6-b002-001a4ae51247 10.1074/jbc.272.2.977 Chlorzoxazone inhibited all three human NOS isoforms with nearly equal potency. 1 Chlorzoxazone MESH:D002753 hydroxylatesProtein PF:PF04886 ProteinFamily 98431ee4-cbf0-11e5-b0dd-001a4ae51247 10101150 "This lack of correlation in cell type distribution between chlorzoxazone hydroxylation activity and CYP2E1 expression suggests that other enzymes are contributing to chlorzoxazone hydroxylation activity in PT microsomes." 1 MESH:D010208 hydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype 0cad7b0a-cc26-11e5-85cd-001a4ae51247 9531516 Under these conditions, papaverine (400 μM) inhibited theO-dealkylation of 7-ethoxyresorufin by 50% and inhibited the 6-hydroxylation of chlorzoxazone by 15%, as shown in fig.10. 1 CHEBI:28794 activates Chlorzoxazone MESH:D002753 Chemical 804ce00e-bbdd-11e5-8abe-001a4ae51246 PMC4184574 Estimation of contributions of CYP isoforms to the enantioselective metabolism of FT To calculate relative activity factor (RAF) that estimates the contribution of the CYP isoform to a particular metabolic reaction, metabolite formation rates for CYP1A2-catalyzed phenacetinO-dethylation, CYP2A6-catalyzed coumarin 7-hydroxylation, CYP2C19-catalyzedS-mephenytoin 4′-hydroxylation, and CYP2E1-catalyzed chlorzoxazone 6-hydroxylation were determined with human hepatic microsomes and cDNA-expressed CYP isoforms. 1 CHEBI:50378 inhibits Chlorzoxazone MESH:D002753 Chemical c599b0b8-f56f-11eb-81a4-001a4a160175 30443705 However, nitisinone slightly reduced the exposure of the CYP2E1 substrate chlorzoxazone, indicating that this enzyme is weakly induced by nitisinone or that the absorption of chlorzoxazone is affected by nitisinone. 1 CHEBI:85103 inhibits Chlorzoxazone MESH:D002753 Chemical c88f121e-3549-11e8-8f56-001a4a160175 18403144 Through thisin vivostudy, we find PITC decreases the activity of CYP 1A2, 3A4 and 2E1, prolonging thet1/2of caffeine, dapsone, and chlorzoxazone. 1 FPLX:CYP hydroxylatesProtein Chlorzoxazone MESH:D002753 ProteinFamily 33058d06-ab9b-11e6-90f5-001a4ae51247 26228688 EthoxyresorufinO-deethylation, 7-ethoxycoumarinO-deethylation, coumarin 7-hydroxylation, 7-pentoxyresorufinO-deethylation, paclitaxel 6α-hydroxylation, diclofenac 4′-hydroxylation, tolbutamide methylhydroxylation, flurbiprofen 4-hydroxylation,S/R-warfarin 7-hydroxylation, omeprazole 5-hydroxylation, chlorzoxazone 6-hydroxylation, bufuralol 1′-hydroxylation, and midazolam 1′-hydroxylation by recombinant P450 2C proteins and liver microsomes from marmosets, cynomolgus monkeys, and humans were measured as described previously (Yamazaki et al., 2002;Uno et al., 2011b) with some minor changes. 1 FPLX:CYP activates Chlorzoxazone MESH:D002753 ProteinFamily b7bdef7c-dbdc-11ea-a071-001a4a160175 PMC7071109 In this systematic study, the in vitro inhibitory effect of salicylic acid on CYP2E1 enzyme activity was evaluated to determine the potency of salicylic acid in affecting CYP mediated phase 1 metabolism in male rat microsomes, employing chlorzoxazone as a probe substrate for the CYP2E1 enzyme in the presence of different concentrations of salicylic acid. 1 FPLX:CYP inhibits Chlorzoxazone MESH:D002753 ProteinFamily c595a2a2-3950-11e8-9fbf-001a4a160176 19000661 In addition, fructose/hydroperoxide cytotoxicity, mitochondrial toxicity, and ROS formation were prevented by the P450 suicide general inhibitor aminobenzotriazole (ABT) or the CYP2E1 inhibitors phenylimidazole (PI) and chlorzoxazone (CLX), as shown inTable 3. 1 FPLX:CYP activates Chlorzoxazone MESH:D002753 ProteinFamily 81adb398-bc27-11e5-8abe-001a4ae51246 10.1016/j.phymed.2010.05.003 In this study, the effects of tanshinones (tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone (Fig. 1), on human CYP1A2, 2C9, 2E1 and 3A4 catalytic activity was investigatedin vitroto determine the potential of Danshen in affecting CYP mediated phase I metabolism in human, using phenacetin (CYP1A2), tolbutamide (CYP2C9), chlorzoxazone (CYP2E1) and testosterone (CYP3A4) as the respective probe substrates. 1 MESH:D003022 inhibits Chlorzoxazone MESH:D002753 Phenotype 15177008-cb2b-11e5-b419-001a4ae51246 12237330 The expression of SK2 and SK4 in HEK293 cells was confirmed by RT-PCR using subtype-specific primers and was verified functionally by membrane hyperpolarization induced by chlorzoxazone, which was then blocked by apamin and clotrimazole, respectively. 1 MESH:D001599 inhibits Chlorzoxazone MESH:D002753 Phenotype 15ebe86e-3814-11e6-9aa8-001a4ae51247 25609220 "Chen et al. have shown that berberine inhibits chlorzoxazone and dextromethorphan metabolism, implying that berberine inhibits CYP2E1 and CYP2D6, respectively (Chen et al., 2013)." 1 CHEBI:15843 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Chemical d23c1026-bc4e-11e5-8d2d-001a4ae51247 10.1016/j.prostaglandins.2009.02.003 It was found that arachidonic acid inhibited 6-hydroxylation of chlorzoxazone by 47%. 1 CHEBI:63959 activates Chlorzoxazone MESH:D002753 Chemical 014fd712-3533-11e8-87fd-001a4a160176 24144799 In this study, the effects of celastrol on the above-mentioned CYPs activities were investigatedin vitroto determine the potential of celastrol in affecting CYP mediated phase I metabolism in rats, employing phenacetin (CYP1A2), tolbutamide (CYP2C11), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and testosterone (CYP3A2) as the probe substrates. 1 UNIPROT:P00167 inhibits Chlorzoxazone MESH:D002753 Protein fa7edbbe-c468-11e5-9da3-001a4ae51247 PMC3935460 "Cyb5 deletion caused the AUC of chlorzoxazone (a Cyp2e1 substrate) to increase 2.1-fold along with a 55% reduction in drug clearance, while in the case of phenacetin (a Cyp1a2 substrate) AUC was increased 1.8-fold and clearance and half-life were both reduced to 55–65% of wild-type rates." 1 CHEBI:29108 activates Chlorzoxazone MESH:D002753 Chemical 3add5a18-5c8f-11e7-8e96-001a4ae51246 PMC4922606 Injections with a positive modulator of SK-type calcium-activated potassium channels (chlorzoxazone) can normalize the firing pattern of SCA2 PCs in vivo. 1 MESH:D000096 activates Chlorzoxazone MESH:D002753 Phenotype 8f2c23fc-c47d-11e5-9cc6-001a4ae51246 20729275 "However, for acetone, the inhibitory effect did not follow the usual organic solvent concentration-dependent inhibition at concentration of 1 to 5% v/v, whereas it was reported previously that acute acetone (5% v/v) treatments increased chlorzoxazone activity by 3.1-fold with Wistar rats (González-Jasso et al., 2003)." 1 UNIPROT:P33261 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 6b3b4714-3755-11e8-a34b-001a4a160175 25936586 CTXA showed a weak inhibition of CYP2C19-catalyzed omeprazole 5-hydroxylation and CYP2E1-catalyzed chlorzoxazone 6-hydroxylation in 5 min preincubated HLM with an IC50value of 9.9 ± 2.2 and 14.4 ± 3.7 µM, respectively. 1 MESH:D010455 activates Chlorzoxazone MESH:D002753 Phenotype e853d220-cb28-11e5-8189-001a4ae51246 11404241 In the present study, the N-K4-M2GlyR peptide enhanced Cl−secretion when added to CFT1 cells together with chlorzoxazone. 1 CHEBI:53329 activates Chlorzoxazone MESH:D002753 Chemical 1ff6852e-c46c-11e5-91a7-001a4ae51247 24727486 In rats ABT has been shown to increase the oral exposure of midazolam by ∼100-fold (Strelevitz et al., 2006) and chlorzoxazone by 3- to 4-fold (Muzeeb et al., 2005). 1 UNIPROTPRO:PRO:0000014901 activates Chlorzoxazone MESH:D002753 Protein 755a5f3a-390a-11e8-a51f-001a4a160176 25091466 The result demonstrated that single dose of alcoholic extract (1-h SC treatment) had no obvious effect on chlorzoxazone PK profile, while multiple dosages (7-day SC treatment) accelerated the metabolism of chlorzoxazone, indicated by the obvious changes of AUC and CLz/F, through the induction of CYP2E1 activity, mRNA and protein expression. 1 UNIPROT:P04798 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 0cad7b0a-cc26-11e5-85cd-001a4ae51247 9531516 The 6-hydroxylation of chlorzoxazone can also be catalyzed by CYP1A1 (Carriereet al., 1993;Yamazakiet al., 1995), but this enzyme is rarely if ever expressed in human liver (Murrayet al., 1993;Schweiklet al., 1993). 1 UNIPROT:P04798 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein d53941f4-cc93-11e5-888a-001a4ae51246 9152602 "CYP1A1 was also active for the 6-hydroxylation of chlorzoxazone, though lower than CYP2E1 did." 1 MESH:D007035 activates Chlorzoxazone MESH:D002753 Phenotype dc9e060c-c47b-11e5-a92e-001a4ae51246 21371018 In animals, hypothermia has been demonstrated to increase the plasma concentration and the half-life of chlorzoxazone (Tortorici et al., 2006), fentanyl (Koren et al., 1987), gentamicin, theophylline (Koren et al., 1985), and morphine (Bansinath et al., 1988), mostly by reducing their clearance. 1 CHEBI:2981 inhibits Chlorzoxazone MESH:D002753 Chemical 0712ba46-bee5-11e5-babb-001a4ae51247 10.1016/j.cbi.2013.02.005 The result was very different from our recent report[42]which showed baicalin only inhibited chlorzoxazone (CYP2E1 probe substrate) in RLMs and did not change the AUC and CL of chlorzoxazone in rats. 1 CHEBI:16474 hydroxylatesProtein Chlorzoxazone MESH:D002753 Chemical fd855fb4-cca5-11e5-aade-001a4ae51247 9058590 "The CYP2E1-dependent catalytic activities were determined by measuring NADPH-dependent hydroxylation of chlorzoxazone in 10,000 ×gsupernatants of the transfected cells." 1 MESH:D013217 inhibits Chlorzoxazone MESH:D002753 Phenotype 3af4a824-bbde-11e5-8abe-001a4ae51246 10.1016/j.aquatox.2008.08.016 Starvation increased chlorzoxazone 6-hydroxylase activity by 2-fold (a CYP2E1 activity) but did not result in any change in ethoxy-resorufin-O-deethylase activity (a CYP1A1 activity) in winter flounder,Pleuronectes americanus(Wall and Crivello, 1999). 1 UNIPROT:P05177 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 0cad7b0a-cc26-11e5-85cd-001a4ae51247 9531516 "Onoet al.(1995)suggested that CYP1A2 contributes to the 6-hydroxylation of chlorzoxazone by human liver microsomes, particularly at low substrate concentrations." 1 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 8a027d0e-ca5e-11e5-a3f7-001a4ae51246 14570761 6-Hydroxylation of chlorzoxazone is catalyzed primarily by CYP2E1 (Peter et al., 1990;Lucas et al., 1996); therefore, the chemical probe would offer a simple and fast method for measuring CYP2E1 induction in cell culture. 1 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein fb0cbce2-cbf0-11e5-83a8-001a4ae51246 10490907 "Similarly, in humans, a single DSF dose reduced CYP2E1-mediated chlorzoxazone 6-hydroxylation to less than 10% of baseline values within 24 h (Kharasch et al., 1993)." 1 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein d741a85c-cb8e-11e5-984a-001a4ae51247 11046114 "The 6-hydroxylation of chlorzoxazone was also reported to be catalyzed primarily by CYP2E1 in human liver microsomes and had been used both in vivo and in vitro as a specific probe for CYP2E1 activity (Lucas et al., 1996;Amato et al., 1998)." 1 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 8da667d0-ca00-11e5-be63-001a4ae51246 15728263 The rate of chlorzoxazone 6-hydroxylation by CYP2E1 was enhanced 2-fold by b5. 1 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein 804ce00e-bbdd-11e5-8abe-001a4ae51246 PMC4184574 Estimation of contributions of CYP isoforms to the enantioselective metabolism of FT To calculate relative activity factor (RAF) that estimates the contribution of the CYP isoform to a particular metabolic reaction, metabolite formation rates for CYP1A2-catalyzed phenacetinO-dethylation, CYP2A6-catalyzed coumarin 7-hydroxylation, CYP2C19-catalyzedS-mephenytoin 4′-hydroxylation, and CYP2E1-catalyzed chlorzoxazone 6-hydroxylation were determined with human hepatic microsomes and cDNA-expressed CYP isoforms. 1 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein 0cad7b0a-cc26-11e5-85cd-001a4ae51247 9531516 "Furthermore,Carriereet al.(1993)reported that, at a substrate concentration of 400 μM, the turnover number for chlorzoxazone 6-hydroxylation by CYP2E1 is 10 times greater than that for CYP1A1 (25vs.2.5 min-1)." 1 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein e18815b0-c8de-11e5-9624-001a4ae51246 16434548 Cigarette smoking accelerates chlorzoxazone metabolism in humans, most likely by induction of hepatic CYP2E1 activity (Benowitz et al., 2003). 1 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein ea9fc70e-ca5c-11e5-8050-001a4ae51246 12750430 "In addition, we have demonstrated that nicotine does not inhibit CYP2E1 hydroxylation of chlorzoxazone in rat liver microsomes (Howard et al., 2001)." 1 UNIPROT:P05181 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein b2aa66a4-bc03-11e5-8abe-001a4ae51246 10.1016/S0278-6915(00)00119-8 One group (Peter et al., 1990) showed that the 6-hydroxylation of chlorzoxazone by CYP2E1 could be monitored and used as a specific probe to measure CYP2E1 activity in liver. 1 UNIPROT:P05181 activates Chlorzoxazone MESH:D002753 Protein dc572276-c478-11e5-85e4-001a4ae51246 PMC3156825 In fact, the increased expression of Cyp2e1 gene in the liver of HFD mice has been shown to mediate the rapid disposition of chlorzoxane, a muscle relaxant, thus, decreasing its duration of action (Khemawoot et al., 2007). 1 UNIPROT:P05181 inhibits Chlorzoxazone MESH:D002753 Protein 79d33500-c481-11e5-85e4-001a4ae51246 22613176 Inhibition of CYP2E1-mediated chlorzoxazone hydroxylase activity by AMAP was both time- and NADPH-dependent (Fig. 2A). 1 MESH:D004121 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype 50aea806-f0c6-11ee-b346-0050569a791b 10.1016/S0887-2333(03)00049-3 This compound is of particular interest here, since 2% DMSO has been reported to cause a 90% inhibition of chlorzoxazone 6-hydroxylation by human hepatocytes (Easterbrook et al., 2001). 1 MESH:D000077604 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Phenotype 0cad7b0a-cc26-11e5-85cd-001a4ae51247 9531516 As shown in fig.7, 4-methylpyrazole inhibited the 6-hydroxylation of [14C]chlorzoxazone noncompetitively with aKivalue of 2.5 μM, regardless of whether 6-hydroxychlorzoxazone was quantified by the solvent extraction or HPLC procedure. 1 CHEBI:16227 inhibits Chlorzoxazone MESH:D002753 Chemical c8ee10a4-bc54-11e5-8abe-001a4ae51246 10.1016/S1532-0456(00)00177-0 On the other hand, pyridine, a relatively specific CYP2E1 inhibitor in human and rodent liver microsomes (Päivi Taavitsainen, unpublished data), inhibited a portion of chlorzoxazone 6-hydroxylase activity in seal liver microsomes. 1 CHEBI:351346 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Chemical bd0141b4-c463-11e5-85e4-001a4ae51246 PMC3608457 "In addition to the animal studies, studies in humans have demonstrated that a single ingestion of watercress, one of the major sources of PEITC, inhibited the hydroxylation of chlorzoxazone, an in vivo probe for human CYP2E1 activity (Leclercq et al., 1998)." 1 CHEBI:351346 activates Chlorzoxazone MESH:D002753 Chemical b56da6b6-cb27-11e5-8189-001a4ae51246 11353744 Studies byLeclercq et al. (1998)support PEITC-mediated inhibition of P450 2E1-catalyzed chlorzoxazone metabolism in vivo, andMoreno and Hollenberg (1999)reported PEITC inhibition of purified P450 2E1. 1 CHEBI:2120 dehydroxylatesProtein Chlorzoxazone MESH:D002753 Chemical bcae557c-351c-11e8-8636-001a4a160175 28527119 Although both peroxides, H2O2andt-HBP, hydroxylated both substrates, only rCPR and PDR/Pdx among four reductase systems could support the 4-NP hydroxylation but not chlorzoxazone hydroxylation. 1 UNIPROT:Q874I5 activates Chlorzoxazone MESH:D002753 Protein e68c1578-c8e5-11e5-9ad8-001a4ae51247 17693640 Chlorzoxazone metabolism by cyt P450 2E1 is also stimulated by cytb5, but not by apo-cytb5, in a purified reconstituted system as well as in membranes in which cyt P450 2E1 and CPR have been coexpressed (8,9). 1 UNIPROT:P51538 hydroxylatesProtein Chlorzoxazone MESH:D002753 Protein d741a85c-cb8e-11e5-984a-001a4ae51247 11046114 "Our data show that CYP3A9 is active in the 6-hydroxylation of chlorzoxazone with a turnover number 1.3 nmol/min/nmol of P450." 1 UNIPROT:P51538 inhibits Chlorzoxazone MESH:D002753 Protein d741a85c-cb8e-11e5-984a-001a4ae51247 11046114 The time course of recombinant purified CYP3A9-catalyzed chlorzoxazone turnover is shown in Fig.3.