1996 Fiscal Year Final Research Report Summary
Studies on prediction of fetal toxicity caused by drugs.
| Project/Area Number |
07457557
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Chiba University |
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Principal Investigator |
KITADA Mitsukazu Chiba University, Hospital Pharmacy, Professor, 医学部・附属病院, 教授 (90110345)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Itsuko Chiba University, Clincal Pharmacology, Assistant, 薬学部, 助手 (00202929)
OHMORI Shigeru Chiba University, Hospital Pharmacy, Associate Professor, 医学部・附属病院, 助教授 (70169069)
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| Project Period (FY) |
1995 – 1996
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| Keywords | CYP enzymes / CYP3A7 / steroid metabolism / drug metabolism / expression in COS-7 cells and TN-5 cells |
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| Research Abstract |
Human CYP3A enzymes (CYP3A4, CYP3A5, CYP3A7) expressed in COS-7 cells and CYP3A7 expressed in TN-5 cells using baculovirus were used for the characterization of human fetal cytochrome P450 (CYP3A7). CYP3A4 showed the highest activity towards to testosterone 6beta-hydroxylation. In contrast, CYP3A7 showed the highest activities for 16alpha-hydroxylation of dehydroepiandrosterone and its 3-sulfate. CYP3A5 was inactive for 16alpha-hydroxylation of dehydroepiandrosterone and its 3-sulfate. CYP3A7 catalyzed the formations 10,11-epoxide from carbamazepine, and 2-sulphamoylacetylphenol from zonisamide though CYP3A4 was the most active for both reactions. Triazolam inhibited testosterone 6b-hydroxylation catalyzed by both CYP3A5 and CYP3A7 at the concentration of which triazolam did not affect the reaction catalyzed by CYP3A4. In addition, triacetyloleandomycin exerted inhibitory effects on testosterone 6beta-hydroxylation depending on the time of microsomes with the drug in the presence of NADPH.However, the inhibitory effect of triacetyloleandomycin was pronounced in CYP3A4-mediated reaction compared to that catalyzed by CYP3A5 of CYP3A7. Although the Vmax of 16a-hydroxylation of dehydroepiandrosterone was about 10 times higher than that of 3-sulfate derivative, Km for the reactions were not different from each other. CYP3A7 also active for cortisol 6beta-hydroxylation. However, Vmax/Km or cortisol 6beta-hydroxylation was extremely low compared to those of 16alpha-hydroxylation of dehydroepiandrosterone and its 3-sulfate.
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[Publications] S.Narimatsu, M.Gotoh, Y.Masubuchi, T.Horie, S,Ohmori, M.Kitada, T.Kageyama, K.Asaoka, I.Yamamoto, T.Suzuki: "Stereoselectivity in bunitorolol 4-hydroxylation in liver microsomes from Mamosets and Japanese monkeys." Biol.Pharm.Bull.19. 1429-1433 (1996)
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