SUPPRESSION OF MALE-SPECIFIC CYTOCHROME-P450 ISOFORMS BY BISPHENOL-A IN RAT-LIVER

We examined the effect of bisphenol A (BPA) on microsomal cytochrome P 450 (P450) enzymes in rats. Rats were treated intraperitoneally with B PA daily for 4 days, at doses of 10, 20, and 40 mg/kg. Among the P450- dependent monooxygenase activities, testosterone 2 alpha-hydroxylase ( T2AH) and testosterone 6 beta-hydroxylase (T6BH) activities, which are associated with CYP2C11 and CYP3A2 respectively, were remarkably decr eased by 40 mg/kg BPA. The levels of the control activities were 13 an d 50%, respectively. Furthermore, immunoblotting showed that BPA (20 o r 40 mg/kg) significantly reduced CYP2C11/6 and CYP3A2/1 protein level s 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 K-m values for T2 AH and T6BH in 20 and 40 mg/kg BPA-treated rats were significantly hig h compared with that in control rats. The V-max for T2AH was dose-depe ndently decreased by BPA treatment, whereas that of T6BH was only decr eased by BPA at 40 mg/kg. On the other hand, lauric acid omega-hydroxy lase (LAOH) activity was significantly increased by BPA at 20 and 40 m g/kg (1.5- and 1.7-fold, respectively). Immunoblot analysis showed tha t 20 and 40 mg/kg BPA induced CYP4A1/2 protein expression. However, th e activities 7-ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD), 7-ethoxycoumarin O-deethylase (ECOD), 7-benzylo xyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND), ch lorzoxazone 6-hydroxylase (CZ6H), erythromycin N-demethylase (EMND), a nd testosterone 7 alpha-hydroxylase (T7AH) were not affected by BPA at any dose. These results suggest that BPA affects male-specific P450 i soforms in rat liver, and that these changes closely relate to the tox icity of BPA.