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

Niwa, Toshiyuki; Maekawa, Yumi; Fujimoto, M.; Kishimoto, Kae; Yabusaki, Yoshiyasu; Ishibashi, Fumihide; Katagiri, Masatoshi

doi:10.1248/bpb.25.235

Cited by 14 publications

(11 citation statements)

References 22 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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“…It is not known why NP did not act in a dose-dependent fashion, but it is possible that NP is acting as a P450 inhibitor at higher concentrations. NP has been shown to inhibit P450 activity (Lee et al, 1996;Niwa et al, 2002;Acevedo et al, 2005), including testosterone 16β-hydroxylase activity (Acevedo et al, 2005), which has been assigned to the Cyp2b subfamily members. NP is extensively metabolized by rat and human Cyp2b family members (Lee et al, 1998), so NP may be competing with ZOX for Cyp2b-mediated metabolism.…”

Section: Discussionmentioning

confidence: 99%

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Hernández

Chapman

Kretschmer

et al. 2006

Toxicology and Applied Pharmacology

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Nonylphenol (NP) is a breakdown product of nonylphenol ethoxylates, which are used in a variety of industrial, agricultural, household cleaning, and beauty products. NP is one of the most commonly found toxicants in the United States and Europe and is considered a toxicant of concern because of its long half-life. NP is an environmental estrogen that also activates the pregnane X-receptor (PXR) and in turn induces P450s. No study to date has examined the gender-specific effects of NP on hepatic P450 expression. We provided NP at 0, 50 or 75 mg/kg/day for 7 days to male and female FVB/NJ mice and compared their P450 expression profiles. Q-PCR was performed on hepatic cDNA using primers to several CYP isoforms regulated by PXR or its relative, the constitutive androstane receptor (CAR). In female mice, NP induced Cyp2b10 and Cyp2b13, and downregulated the female-specific P450s, Cyp3a41 and Cyp3a44. In contrast, male mice treated with NP showed increased expression of Cyp2a4, Cyp2b9, and Cyp2b10. Western blots confirmed induction of Cyp2b subfamily members in both males and females. Consistent with the Q-PCR data, Western blots showed dose-dependent downregulation of Cyp3a only in females and induction of Cyp2a only in males. The overall increase in female-predominant P450s in males (Cyp2a4, 2b9) and the decrease in female-predominant P450s in females (Cyp3a41, 3a44) suggest that NP is in part feminizing the P450 profile in males and masculinizing the P450 profile in females. Testosterone hydroxylation was also altered in a genderspecific manner, as testosterone 16α-hydroxylase activity was only induced in NP-treated males. In contrast, NP-treated females demonstrated a greater propensity for metabolizing zoxazolamine probably due to greater Cyp2b induction in females. In conclusion, NP causes gender-specific P450 induction and therefore exposure to NP may cause distinct pharmacological and toxicological effects in males compared to females.

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“…out according to methods described previously. 10) Assay of Progesterone 17α-Hydroxylation Activity Progesterone 17α-hydroxylation activity was determined by methods described previously 8,9) with minor modification. Briefly, the membrane fraction containing CYP17 (120 pmol) and POR (210 pmol) was preincubated at 37°C for 3 min, and the mixture was brought to 500 µL; the incubation mixture consisted of 100 mM potassium phosphate buffer (pH 7.4), 10 mM magnesium acetate, 1 mM NADPH, 1 µM (for inhibition by various steroids) or 5-100 µM (for estimation of inhibition constants [K i values]) progesterone, and 0, 20, 50, or 100 µM steroid hormone.…”

Section: Methodsmentioning

confidence: 99%

“…As summarized in Table 2, 8,9,[13][14][15] it has been reported that the IC 50 value of abiraterone, which also contains a hydroxyl group at C 3 in the A ring and a double bond at C 5 in the B ring, was 0.072 µM.…”

Section: Fig 2 Inhibitory Effect Of 21-hydroxypregnenolone On Humanmentioning

confidence: 97%

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Inhibition of Human Steroidogenic Cytochrome P450 c17 by 21-Hydroxypregnenolone and Related Steroid Hormones

Niwa

Imamura

Katagiri

2012

Biological & Pharmaceutical Bulletin

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The effects of 21-hydroxypregnenolone and related steroids such as deoxycorticosterone (DOC; 21-hydroxyprogesterone), cortisol, and corticosterone on progesterone 17α-hydroxylase activity by steroidogenic cytochrome P450 c17 (CYP17) were investigated. 21-Hydroxypregnenolone contains a hydroxyl group at C 3 in the A cyclic hydrocarbon ring and a double bond at C 5 in the B cyclic hydrocarbon ring, whereas DOC, cortisol, and corticosterone contain a ketone group at C 3 and a double bond at C 4 in the A cyclic hydrocarbon ring. No marked inhibition was observed for DOC, cortisol, and corticosterone at 100 μM concentration. Nonetheless, 21-hydroxypregnenolone exhibited competitive inhibition of progesterone 17α-hydroxylation activity by CYP17 with a K i value of 36.4 µM. These results suggest that a hydroxyl group at C 3 in the A ring and a double bond at C 5 in the B ring in steroid hormones are important for the substrate recognition of CYP17.Key words cytochrome P450 c17; 21-hydroxypregnenolone; 17α-hydroxylation; deoxycorticosterone; corticosterone; progesterone Cytochrome P450 c17 (CYP17) is found in the endoplasmic reticulum of the adrenal cortex and gonads, and mediates both 17α-hydroxylase and 17,20-lyase reactions of pregnenolone and progesterone, thus being involved in the biosynthesis of glucocorticoids and sex hormones. 1)Various steroid hormones are biotransformed by metabolic enzymes including CYP11 and CYP21 as well as CYP17, in adrenal glands (Fig. 1). Deoxycorticosterone (DOC; 21-hydroxyprogesterone), cortisol, and corticosterone are well known to be important in the principal pathways of steroid hormone synthesis.2) 21-Hydroxypregnenolone has been shown to be biotransformed from pregnenolone in human, rat, and sheep adrenal tissue in vitro, 3,4) although how 21-hydroxypregnenolone is formed in human tissues or organs remains unknown. 21-Hydroxypregnenolone is detectable in urine of newborn human infants 5) and adults, 6) and 21-hydroxypregnenolone excretion is highly elevated in 21-hydroxylase deficiency.7) 21-Hydroxypregnenolone contains a hydroxyl group at C 3 in the A cyclic hydrocarbon ring and a double bond at C 5 in the B cyclic hydrocarbon ring, whereas DOC, cortisol, and corticosterone contain a ketone group at C 3 and a double bond at C 4 in the A ring. In particular, DOC is identical to 21-hydroxypregnenolone except at C 3 , C 4 , and C 5 positions. Thus there is a possibility that biotransformed steroid hormones might affect human steroidogenesis in the adrenal gland.We previously demonstrated that endocrine disrupters such as bisphenol A and nonylphenol exhibited competitive inhibition of progesterone 17α-hydroxylation by human CYP17. 8,9) In the present study we investigated the inhibitory effects of 21-hydroxypregnenolone, DOC, cortisol, and corticosterone on catalytic activity of recombinant human CYP17 expressed in Escherichia coli membrane fractions.

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

Cited by 14 publications

References 22 publications

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

Inhibition of Human Steroidogenic Cytochrome P450 c17 by 21-Hydroxypregnenolone and Related Steroid Hormones

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