Studies on the Interactions between Drugs and Estrogen: Analytical Method for Prediction System of Gynecomastia Induced by Drugs on the Inhibitory Metabolism of Estradiol Using Escherichia coli Coexpressing Human CYP3A4 with Human NADPH-Cytochrome P450 Reductase
✍ Scribed by Takashi Satoh; Ken-ichi Fujita; Haruka Munakata; Shinji Itoh; Katsunori Nakamura; Tetsuya Kamataki; Shungo Itoh; Itsuo Yoshizawa
- Publisher
- Elsevier Science
- Year
- 2000
- Tongue
- English
- Weight
- 94 KB
- Volume
- 286
- Category
- Article
- ISSN
- 0003-2697
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✦ Synopsis
To establish a prediction system for drug-induced gynecomastia in clinical fields, a model reaction system was developed to explain numerically this side effect. The principle is based on the assumption that 50% inhibition concentration (IC 50 ) of drugs on the in vitro metabolism of estradiol (E2) to its major product 2-hydroxyestradiol (2-OH-E2) can be regarded as the index for achieving this purpose. By using human cytochrome P450s coexpressed with human NADPH-cytochrome P450 reductase in Escherichia coli as the enzyme, the reaction was examined. Among the nine enzymes (CYP1A1, 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) tested, CYP3A4 having a V max /K m (ml/min/ nmol P450) value of 0.32 for production of 2-OH-E2 was shown to be the most suitable enzyme as the reagent. The inhibitory effects of ketoconazole, cyclosporin A, and cimetidine toward the 2-hydroxylation of E2 catalyzed by CYP3A4 were obtained, and their IC 50 values were 7 nM, 64 nM, and 290 M, respectively. The present results suggest that IC 50 values thus obtained can be substituted as the prediction index for gynecomastia induced by drugs, considering the patients' individual information.