Interaction of nonylphenol and hepatic CYP1A in rats

Lee, Ping C.; Patra, Sharmistha Chakraborty; Stelloh, Cary; Lee, Winnie; Struve, Mark

doi:10.1016/0006-2952(96)00409-1

Cited by 55 publications

(24 citation statements)

References 14 publications

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“…Finally, nonylphenol has been shown to reduce the level of CYP1A1 expression in murine Hepa-1c1c7 cells (Jeong et al, 2001) and to inhibit in vitro CYP1A1 activity in rat liver microsomes (Lee et al, 1996) and activities of human cytochrome P450s, including steroidogeneic CYP17 activities (Niwa et al, 2002). Oral administration of nonylphenol decreased hepatic testosterone hydroxylation and CYP2C expression level (Laurenzana et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Daidoji¹,

Inoue²,

Kato³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Nonylphenol, an environmental estrogenic chemical, is reported to have adverse effects on the reproductive organs of animals. In this study, the metabolism of nonylphenol and that of other alkylphenols in the rat liver was investigated using liver perfusion. Alkylphenols (nonylphenol, hexylphenol, butylphenol, and ethylphenol) were glucuronidated by rat liver microsomes. Nonylphenol was found to be conjugated with glucuronic acid by an isoform of UDP-glucuronosyltransferase, UGT2B1, expressed in yeast AH22 cells. However, when nonylphenol was perfused into rat liver in situ, it was difficult for free nonylphenol and conjugated metabolite to be excreted into the bile or vein, and most of the perfused nonylphenol remained free and as a glucuronide conjugate in the liver tissue, even after 1 h of perfusion. After 1 h of perfusion of the other alkylphenols, most of them were excreted into the bile as glucuronides. Ethylphenol, which has the shortest alkyl chain, was excreted rapidly into both the bile and vein; however, the excretion rates of alkylphenols having longer alkyl chains tended to be slow. MRP-2-deficient Eisai hyperbilirubinemic rats could not secrete alkylphenol-glucuronides into the bile, indicating that alkylphenolglucuronides are transported by MRP-2 to the bile in normal Sprague-Dawley rats. The results indicate that the kinetics of excretion of alkylphenol-glucuronides into the bile or vein depends on the length of alkyl chain and suggest that nonylphenol-glucuronide formed in the liver cannot be transported by MRP-2.Environmental estrogenic chemicals such as bisphenol A and nonylphenol, which are contained in many industrial products, can be detected in foods, tap water, and many environmental materials. Nonylphenol is used in a wide variety of detergents and plastics and has been reported to be environmentally persistent (White et al., 1994). The mean daily oral intake of nonylphenol by humans is estimated to be 0.16 mg/day (Muller et al., 1998). Nonylphenol has been shown to be a possible endocrine disrupter due to its estrogenic effects in MCF7 cell proliferation assays (Soto et al., 1991), binding assays to the estrogen receptor (White et al., 1994) and uterotropic assays in mice (Shelby et al., 1996). Exposure of male rainbow trout (Oncorhynchus mykiss) to four different alkylphenolic chemicals, including nonylphenol, resulted in synthesis of vitellogenin, a process normally dependent on endogenous estrogens, and a concomitant inhibition of testicular growth (Jobling et al., 1996). Male and female ratios of Japanese medaka (Oryzias latipes) in a control group (2:1) and a 100 g/l nonylphenol treatment group (1:2) were reported to be significantly different (Gray and Metcalfe, 1997). Early neonatal exposure to nonylphenol has been reported to cause dysfunction of postpubertal reproductive function in female rats as well as disrupted development of gonads in male and female rats (Nagao et al., 2000). It has also been repor...

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Section: Discussionmentioning

confidence: 99%

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Daidoji¹,

Inoue²,

Kato³

et al. 2003

Drug Metab Dispos

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“…To our knowledge, only a few studies have been reported concerning the metabolic fate of NP in mammalian species. Extensive studies by Lee et al (1996aLee et al ( ,b, 1998 using rat or human liver microsomes have been published. However, these studies did not aim to identify the metabolites of NP formed in vitro but focused on the interactions of NP and hepatic cytochrome P450.…”

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confidence: 99%

In Vivo Metabolic Fate of the Xeno-Estrogen 4-n-Nonylphenol in Wistar Rats

Zalko¹,

Costagliola²,

Dorio³

et al. 2003

Drug Metab Dispos

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ABSTRACT:The distribution and the metabolic fate of 4-n-nonylphenol were investigated in male and female Wistar rats dosed orally with 1 g/kg ("low-dose") or 10 mg/kg ("high-dose") labeled 4-n-nonylphenol. Following a 4-day metabolic balance study, neither the distribution pattern nor the residual levels of 4-n-nonylphenol were found to be different between groups, and no unexpected tissuespecific accumulation of 4-n-nonylphenol was detected. Most of the radioactivity was eliminated in urine, and consisted of hydrophilic metabolites very likely resulting from extensive ␤-oxidation of the nonyl side chain and from the conjugation of the phenol to sulfate or to glucuronic acid. Traces of ring-hydroxylated nonylphenol were also characterized. Fecal excretion was mainly associated with unchanged 4-n-nonylphenol and with side chain hydroxylated 4-n-nonylphenol. Experiments carried out in pregnant rats exposed to a low-dose of 4-n-nonylphenol from day 3 to day 19 of gestation demonstrated similar metabolic pathways for this xeno-estrogen. Very limited amounts, if any, of non metabolized 4-n-nonylphenol did reach fetuses. The oxidative metabolism of 4-n-nonylphenol leads to the formation of both ring-hydroxylated and side chain hydroxylated metabolites. The latter metabolic pathway may be a major metabolic pathway for branched 4-nonylphenols and may be a clue to understand their biological activity.

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“…Our results indicated that nonylphenol could inhibit the drug-metabolizing activities by human hepatic CYPs as well as those in rats, especially CYP1A and CYP2C. 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.…”

Section: Discussionmentioning

confidence: 71%

“…Additionally, they reported that nonylphenol competitively inhibited 7-ethoxyresorufin O-deethylase activity (CYP1A) by hepatic microsomes from b-naphthoflavone-treated rats. 10) We investigated the effect of nonylphenol on the human CYP activities using aminopyrine as a substrate, because most of the CYPs showed the aminopyrine N-demethylase activity.…”

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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Interaction of nonylphenol and hepatic CYP1A in rats

Cited by 55 publications

References 14 publications

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

In Vivo Metabolic Fate of the Xeno-Estrogen 4-n-Nonylphenol in Wistar Rats

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

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