Metabolism and Interaction of Bisphenol A in Human Hepatic Cytochrome P450 and Steroidogenic CYP17.

Abstract

Bisphenol A (4,4Ј-isopropylidenediphenol, BPA) is widely used in the chemical industry in the manufacturing of epoxy, polycarbonate, and polyester-styrene resins, and trace levels of BPA leach from polycarbonate plasticware and resins used for food packaging materials. This compound is suspected to be an endocrine disrupter. 2) Additionally, it has been reported that exposure of male rats and mice to BPA may be associated with increased incidence of cancers of the hematopoietic system and that high doses of BPA cause reproductive toxicity and affect cellular development in these species. 3,4) However, the effect of BPA in vivo and its mechanism of action are still unclear.Cytochrome P450 (CYP) comprises a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs, carcinogens, and steroids including sex hormones. [5][6][7] In the rat, BPA is metabolized to DNA-reactive bisphenol-o-quinone through 5-hydroxybisphenol and bisphenol semiquinone, 4) and the formation of the DNA adducts in a microsomal activation system is markedly decreased by CYP inhibitors, 8) suggesting that CYPs are closely associated with the metabolism and toxicity of BPA in rats. However, there are few reports on BPA metabolism in humans and on the human CYP(s) that metabolizes BPA.Recently, we reported that BPA inhibits human hepatic CYP-mediated drug-metabolizing activities including aminopyrine N-demethylation, especially by CYP2C8 and CYP2C19. 9) Additionally, Hanioka et al. reported that the administration of BPA to male rats decreased the catalytic activities and protein levels of male-specific CYP isoforms (such as CYP2C11 and CYP3A2) in rat liver microsomes, 10) and that BPA inhibited the drug-metabolizing activities of rat hepatic CYP1A2, CYP2A2, CYP2B2, CYP2C11, CYP2D1, CYP2E1, and CYP3A2. 11) CYP17 is found in the endoplasmic reticulum of the adrenal cortex and gonads, and mediates both 17a-hydroxylase and 17,20-lyase reactions of pregnenolone and progesterone, and is thus involved in the biosynthesis of glucocorticoids and sex hormones. 12) Therefore endocrine disrupters (sex hormone-like compounds) may affect the activity of CYP17. Recently, we reported that the aminopyrine Ndemethylase activity of CYP17 was comparable with that of CYP3A4, a dominant CYP in human liver. 13) This paper describes an in vitro investigation of BPA metabolism by human hepatic CYPs and steroidogenic CYP17 based on the disappearance rate of parent compounds from an incubation mixture and the inhibitory effect of BPA on the progesterone 17a-hydroxylase activity of CYP17. MATERIALS AND METHODS MaterialsBisphenol A was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Progesterone, 17a-hydroxyprogesterone, and estrone were from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Human NADPH-cytochrome P450 reductase (fp 2 ) and hydrocortisone acetate were obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). All other reagents were of the highest purity commercially available. Expression o...

Inhibition of Human Hepatic Cytochrome P450s and Steroidogenic CYP17 by Nonylphenol.

“…9,10) We have reported that bisphenol A exhibited a noncompetitive-type inhibition of aminopyrine N-demethylation by CYP2C8, a mixed-type inhibition of S-mephenytoin 4Ј-hydroxylation by CYP2C19, and a competitive-type inhibition of progesterone 17a-hydroxylation by CYP17 with K i values of 97, 113, and 71 mM, respectively. 16,17) The K i values of nonylphenol on diclofenac 4Ј-hydroxylaytion by CYP2C9, Smephenytoin 4Ј-hydroxylation by CYP2C19 and progesterone 17a-hydroxylation by CYP17 were 5.3 mM, 37 mM and 62 mM, respectively (Figs. 2-4).…”

“…16,17) In the present study, we investigated the inhibitory effect of nonylphenol on hepatic CYPs and steroidogenic CYP17 using the cDNA-expressed P450s.…”

“…17) For standard incubation, the final reaction mixture (0.5 ml) contained yeast microsomes (50 pmol CYP), 20-100 mM S-mephenytoin, 1 mM NADPH, and 100 mM Tris-HCl buffer (pH 7.5). After a 2 min preincubation at 37°C, the reaction was started by adding NADPH.…”

“…Assay of Progesterone 17a a-Hydroxylase Activity Progesterone 17a-hydroxylase activity was determined by the methods described previously 7,17) with minor modification. Briefly, the membrane fraction containing CYP17 (30 pmol) and fp 2 (210 pmol) were preincubated at 37°C for 3 min, and the mixture was brought to 450 ml by addition of 100 mM phosphate buffer (pH 7.4), 10 mM magnesium acetate, and 2-50 mM progesterone.…”

Glyphosate, pathways to modern diseases IV: cancer and related pathologies

“…CYP enzymes are also involved with the metabolism of nonylphenols [220]. Similarly, BPA is mainly metabolized by the CYP2C subfamily in the liver [221]. Thus, impaired CYP function due to glyphosate exposure [11,157,158] can be expected to interfere with metabolism of PCBs and therefore increase their oestrogenic potential, leading indirectly to increased risk of breast cancer.…”