Inhibition of Drug-Metabolizing Enzyme Activity in Human Hepatic Cytochrome P450s by Bisphenol A.

Niwa, Toshiyuki; Tsutsui, Miki; Kishimoto, Kae; Yabusaki, Yoshiyasu; Ishibashi, Fumihide; Katagiri, Masatoshi

doi:10.1248/bpb.23.498

Cited by 25 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Niwa

Maekawa

Fujimoto

et al. 2002

Biological & Pharmaceutical Bulletin

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Endocrine disrupters are exogenous substances which can influence endocrine function in humans and animals, and a number of these chemicals, termed "xenoestrogens", have estrogenic activity. Artificial xenoestrogens include the alkylphenols, nonylphenol and octylphenol, and bisphenol A. 2,3) Alkylphenol polyethoxylates are widely used as detergents, emulsifiers, and wetting agents in industry. In the environment, nonylphenol occurs predominantly as a degradation product of nonylphenol ethoxylate. 4)Cytochrome P450s (CYP) comprise a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs and carcinogens, and steroids including sex hormones. 5-7) Lee et al. 8) reported that the metabolism of nonylphenol by rat hepatic microsomes was induced by phenobarbital; the activity was inhibited by 4-amino-2,6-dinitro-1-t-butylxylene, a specific CYP2B inhibitor, and that human CYP2B6 metabolized nonylphenol. Additionally, nonylphenol inhibited progesterone 6b-hydroxylase activity and 7-ethoxyresorufin O-deethylase activity by hepatic microsomes from dexamethazone-and b-naphthoflavone-treated rats, respectively. 9,10) However, there are no reports describing the effect of nonylphenol on human hepatic CYP-mediated drug-metabolizing activity.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, thus being involved in the biosynthesis of glucocorticoids and sex hormones.11) Therefore, endocrine disrupters (sex hormone-like compounds) may affect the activity of CYP17.Recently the heterologous expression systems for human CYPs have been developed in Escherichia coli, in the yeast Saccharomyces cerevisiae, and in human Hep G2 cells, and these genetic technologies have been shown to be very useful in determining the metabolism of xenobiotics by different CYPs. [12][13][14] We reported that the aminopyrine N-demethylation process is metabolized by most of the human hepatic CYPs measured, 15) indicating that this is useful to investigate the effect of inhibitors on human hepatic CYPs.16) Additionally, 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) In the present study, we investigated the inhibitory effect of nonylphenol on hepatic CYPs and steroidogenic CYP17 using the cDNA-expressed P450s. MATERIALS AND METHODSMaterials n-Nonylphenol, aminopyrine, hydrocortisone acetate and human NADPH-cytochrome P450 reductase (fp 2 ) were purchased from Wako Pure Chemical Industries, Ltd. Estrone, progesterone and 17a-hydroxyprogesterone were obtained from Sigma Chemical Co. 4Ј-Hydroxydiclofenac, S-mephenytoin and 4Ј-hydroxymephenytoin were purchased from Sumika Chemical Analysis Service, Ltd., and diclofenac was from Ultrafi...

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Section: Discussionmentioning

confidence: 99%

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

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confidence: 99%

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

Niwa

Maekawa

Fujimoto

et al. 2002

Biological & Pharmaceutical Bulletin

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“…A differential inhibition by BPA has also been observed with human hepatic CYP isoforms in vitro (Niwa et al 2000). Eleven cDNA-expressed CYP forms were probed by aminopyrine N-demethylation.…”

Section: Discussionmentioning

confidence: 99%

“…Hanioka et al (1998Hanioka et al ( , 2000 reported that BPA suppresses various CYP isoforms in hepatic microsomes from male Wistar and Sprague-Dawley rats. When the effect of BPA on 11 different cDNA-expressed human hepatic CYPs was studied by Niwa et al (2000), a strong inhibition of some but not all CYP isoforms was noted.…”

Section: Introductionmentioning

confidence: 99%

Effect of bisphenol A on drug metabolising enzymes in rat hepatic microsomes and precision-cut rat liver slices

Pfeiffer

Metzler

2004

Arch Toxicol

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In order to assess the effects of bisphenol A (BPA) on enzymes of phase I and II biotransformation, studies were conducted in hepatic microsomes and precision-cut liver slices from male Sprague-Dawley rats. A testosterone hydroxylation assay was used for probing the activity of cytochrome P450 (CYP) forms, and an appropriate HPLC method for the separation of testosterone metabolites was developed. BPA markedly inhibited the hydroxylation of testosterone at 2alpha and 16alpha but not at 6beta or 7alpha, suggesting a differential inhibition of some CYP forms, in particular CYP2C11. This inhibitory effect was also observed when slices were first exposed to BPA and then incubated with testosterone in the absence of BPA, indicative of an irreversible inhibition of CYP. In liver slices, a differential conjugation of hydroxylated testosterone metabolites was observed, which was significantly decreased in the presence of BPA. BPA also inhibited the conjugation of the model compound umbelliferone. Pretreatment with BPA did not affect the conjugation of testosterone and umbelliferone. No hydroxylation, but extensive conjugation of BPA was observed upon incubation of liver slices with BPA alone or with testosterone or umbelliferone. The rapid and preferred conjugation, however, does not prevent the irreversible inhibition of some CYP forms by BPA. In conclusion, this study has shown that BPA causes a selective and irreversible inhibition of certain CYP forms and interferes with the conjugation of other drugs.

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“…We have reported the effect of BPA on human hepatic CYP activities using aminopyrine as a substrate, 9) because most CYPs show aminopyrine N-demethylase activity 13) ; the activities of CYPs except for CYP2E1 were inhibited by BPA. Additionally, BPA noncompetitively inhibited the aminopyrine N-demethylase activity by CYP2C8, and exhibited a mixed-type inhibition for S-mephenytoin 4-hydroxylation by CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

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

Niwa

Fujimoto

Kishimoto

et al. 2001

Biological & Pharmaceutical Bulletin

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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...

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Inhibition of Drug-Metabolizing Enzyme Activity in Human Hepatic Cytochrome P450s by Bisphenol A.

Cited by 25 publications

References 0 publications

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

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

Effect of bisphenol A on drug metabolising enzymes in rat hepatic microsomes and precision-cut rat liver slices

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

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