title: Selectivities of human cytochrome P450 inhibitors toward rat P450 isoforms: study with cDNA-expressed systems of the rat.
abstract: The aim of this study was to determine the selectivities of chemical inhibitors for human cytochrome P450 (P450) isoforms toward the corresponding rat P450 isoforms by using cDNA-expressed rat P450s (CYP1A2, CYP2A1, CYP2C6, CYP2C11, CYP2D2, CYP2E1, CYP3A1, and CYP3A2). Among the inhibitor probes for human P450s used in this study, only sulfaphenazole showed a selective inhibitory effect on the activity of the corresponding rat P450 isoform (CYP2C6). Furafylline also preferentially inhibited the activity of rat CYP1A2. However, methoxalen and ketoconazole more strongly inhibited the activities of other P450 isoforms than those of the corresponding rat P450 isoforms, CYP2A1 and CYP3A1/2, respectively. On the other hand, quinidine and aniline had little effect on the activities of the corresponding rat P450 isoforms, CYP2D2, and rat CYP2E1, respectively. These results suggest that chemical probes that have been used for human P450 isoforms do not always exhibit the same selectivity for the corresponding rat P450 isoforms. However, it appears that sulfaphenazole can be used as a selective inhibitor for rat CYP2C6. In addition, furafylline may also be a relatively selective inhibitor for rat CYP1A2.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan. kaoruk@p.chiba-u.ac.jp
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Kikuko
authors.initials: K
authors.lastname: Urashima
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimada
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008730:Methoxsalen / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D013250:Steroid Hydroxylases; D013379:Substrate Specificity / Q000187:drug effects / Q000235:genetics*; D013426:Sulfaphenazole / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013426:Sulfaphenazole; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; C050131:furafylline; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C456179:Cyp2a1 protein, rat; C089877:Cyp2c6v1 protein, rat; C119985:Cyp2d2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013255:Steroid 21-Hydroxylase; D011802:Quinidine; D007654:Ketoconazole; C023650:aniline; D008730:Methoxsalen