Structural requirements of <i>para</i>‐alkylphenols to bind to estrogen receptor

Tabira, Yukiko; Nakai, Makoto; Asai, Daisuke; Yakabe, Yoshikuni; Tahara, Yoshiko; Shinmyozu, Teruo; Noguchi, Masato; Takatsuki, Mineo; Shimohigashi, Yasuyuki

doi:10.1046/j.1432-1327.1999.00422.x

Cited by 89 publications

(55 citation statements)

References 31 publications

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“…One of the toxicological implications for the delay of excretion of nonylphenol and nonylphenol-glucuronide is estimated to the binding to and inhibition of ER (Tabira et al, 1999); another is the inhibition of MRP-2 which excretes various glucuronides such as estradiol glucuronide (Ito et al, 2001) and bilirubin glucuronide (Kusuhara et al, 1998). The delay of nonylphenol excretion is possible because of the adverse effects of nonylphenol on rat reproductive systems (Laws et al, 2000).…”

Section: Fig 5 Excretion Of Alkylphenol Metabolites During Liver Pementioning

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: Fig 5 Excretion Of Alkylphenol Metabolites During Liver Pementioning

confidence: 99%

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Daidoji¹,

Inoue²,

Kato³

et al. 2003

Drug Metab Dispos

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“…1), and it has been suggested that alkylphenols may act as endocrine disrupters by mimicking the activity of 17␤-estradiol at estrogen receptors. Indeed, in a variety of cells transfected with human estrogen receptors, alkylphenols have been shown to bind weakly and provoke modest estrogenic effects (15)(16)(17). Conversely, alkylphenols have been reported to promote estrogenic signaling by inhibiting androgen receptor activation in some tissues (18,19).…”

mentioning

confidence: 99%

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

Harris

Waring

Kirk

et al. 2000

Journal of Biological Chemistry

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We have investigated the ability of alkylphenols to act as substrates and/or inhibitors of phenol sulfotransferase enzymes in human platelet cytosolic fractions. Our results indicate: (i) straight chain alkylphenols do not interact with the monoamine-sulfating phenol sulfotransferase (SULT1A3); (ii) short chain 4-n-alkylphenols (C < 8) are substrates for the phenol-sulfating enzymes (SULT1A1/2), which exhibit two activity maxima against substrates with alkyl chain lengths of C1-2 and C4 -5; (iii) long chain 4-n-substituted alkylphenols (C > 8) are poor substrates and act as inhibitors of SULT1A1/2; (iv) human platelets contain two activities, of low and high affinity, capable of sulfating 17␤-estradiol, and 4-n-nonylphenol is a partial mixed inhibitor of the low affinity form of this activity. We conclude that by acting either as substrates or inhibitors of SULT1A1/2, alkylphenols may influence the sulfation, and hence the excretion, of estrogens and other phenol sulfotransferase substrates in humans.

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“…Only compounds with a 6-10 carbon chain were active, with potencies ranging from 100 nM to 3 M. In addition, the conversion of the hydroxy group on the phenol moiety to a methyl led to a complete loss of activity. Furthermore, the analogous hexyl, heptyl, octyl, and nonyl-phenols reported to be micromolar estrogen receptor ligands were evaluated (Tabira et al, 1999). As expected, they display low-affinity estrogen receptor agonism but, more importantly, lacked any crossover activity at the SF-1 receptor (data not shown).…”

Section: Resultsmentioning

confidence: 86%

Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

Tredici¹,

Andersen²,

Currier³

et al. 2007

Mol Pharmacol

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Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological system of endocrine function, the expression of several reported SF-1 target genes, including SF-1 itself, was inhibited by treatment with AC-45594 and analogs. Thus, pharmacological modulation of SF-1 is critical to its function as an endocrine master regulator and has potentially important consequences to diseases in which SF-1 activity is critical.

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Structural requirements of para‐alkylphenols to bind to estrogen receptor

Cited by 89 publications

References 31 publications

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Glucuronidation and Excretion of Nonylphenol in Perfused Rat Liver

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

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