Suppression of male-specific cytochrome P450 isoforms by bisphenol A in rat liver.
We examined the effect of bisphenol A (BPA) on microsomal cytochrome P450 (P450) enzymes in rats. Rats were treated intraperitoneally with BPA daily for 4 days, at doses of 10, 20, and 40 mg/kg. Among the P450-dependent monooxygenase activities, testosterone 2alpha-hydroxylase (T2AH) and testosterone 6beta-hydroxylase (T6BH) activities, which are associated with CYP2C11 and CYP3A2 respectively, were remarkably decreased by 40 mg/kg BPA. The levels of the control activities were 13 and 50%, respectively. Furthermore, immunoblotting showed that BPA (20 or 40 mg/kg) significantly reduced CYP2C 11/6 and CYP3A2/1 protein levels in rat liver microsomes. In addition, estradiol 2-hydroxylase (ED2H) and benzphetamine N-demethylase (BZND) activities were significantly decreased by BPA at 20 and 40 mg/kg (by 19-73%). The Km values for T2AH and T6BH in 20 and 40 mg/kg BPA-treated rats were significantly high compared with that in control rats. The Vmax for T2AH was dose-dependently decreased by BPA treatment, whereas that of T6BH was only decreased by BPA at 40 mg/kg. On the other hand, lauric acid omega-hydroxylase (LAOH) activity was significantly increased by BPA at 20 and 40 mg/kg (1.5- and 1.7-fold, respectively). Immunoblot analysis showed that 20 and 40 mg/kg BPA induced CYP4A1/2 protein expression. However, the activities 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD), 7-ethoxycoumarin O-deethylase (ECOD), 7-benzyloxyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND), chlorzoxazone 6-hydroxylase (CZ6H), erythromycin N-demethylase (EMND), and testosterone 7alpha-hydroxylase (T7AH) were not affected by BPA at any dose. These results suggest that BPA affects male-specific P450 isoforms in rat liver, and that these changes closely relate to the toxicity of BPA.
Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan.
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Hanioka
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Jinno
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Nishimura
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Ando
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001559:Benzhydryl Compounds; D001835:Body Weight / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000098826:Bisphenol A Compounds
D001189:Aryl Hydrocarbon Hydroxylases; D001559:Benzhydryl Compounds; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D008565:Membrane Proteins; D010089:Oxidoreductases, N-Demethylating; D010636:Phenols; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases; C450279:CYP2C11 protein, rat; C465260:Cyp3a2 protein, rat; C019781:benzphetamine N-demethylase; C022657:steroid hormone 6-beta-hydroxylase; C006780:bisphenol A; D000098826:Bisphenol A Compounds