Inhibitors of Testosterone Biosynthetic and Metabolic Activation Enzymes

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Abstract

The Leydig cells of the testis have the capacity to biosynthesize testosterone from cholesterol. Testosterone and its metabolically activated product dihydrotestosterone are critical for the development of male reproductive system and spermatogenesis. At least four steroidogenic enzymes are involved in testosterone biosynthesis: Cholesterol side chain cleavage enzyme (CYP11A1) for the conversion of cholesterol into pregnenolone within the mitochondria, 3β-hydroxysteroid dehydrogenase (HSD3B), for the conversion of pregnenolone into progesterone, 17α-hydroxylase/17,20-lyase (CYP17A1) for the conversion of progesterone into androstenedione and 17β-hydroxysteroid dehydrogenase (HSD17B3) for the formation of testosterone from androstenedione. Testosterone is also metabolically activated into more potent androgen dihydrotestosterone by two isoforms 5α-reductase 1 (SRD5A1) and 2 (SRD5A2) in Leydig cells and peripheral tissues. Many endocrine disruptors act as antiandrogens via directly inhibiting one or more enzymes for testosterone biosynthesis and metabolic activation. These chemicals include industrial materials (perfluoroalkyl compounds, phthalates, bisphenol A and benzophenone) and pesticides/biocides (methoxychlor, organotins, 1,2-dibromo-3-chloropropane and prochloraz) and plant constituents (genistein and gossypol). This paper reviews these endocrine disruptors targeting steroidogenic enzymes.

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Exposure of the U.S. Population to Bisphenol A and 4-tertiary-Octylphenol: 2003–2004

Antonia M Calafat, Xiaoyun Ye, Lee-Yang Wong … (2007)

Background Bisphenol A (BPA) and 4-tertiary-octylphenol (tOP) are industrial chemicals used in the manufacture of polycarbonate plastics and epoxy resins (BPA) and nonionic surfactants (tOP). These products are in widespread use in the United States. Objectives We aimed to assess exposure to BPA and tOP in the U.S. general population. Methods We measured the total (free plus conjugated) urinary concentrations of BPA and tOP in 2,517 participants ≥ 6 years of age in the 2003–2004 National Health and Nutrition Examination Survey using automated solid-phase extraction coupled to isotope dilution–high-performance liquid chromatography–tandem mass spectrometry. Results BPA and tOP were detected in 92.6% and 57.4% of the persons, respectively. Least square geometric mean (LSGM) concentrations of BPA were significantly lower in Mexican Americans than in non-Hispanic blacks (p = 0.006) and non-Hispanic whites (p = 0.007); LSGM concentrations for non-Hispanic blacks and non-Hispanic whites were not statistically different (p = 0.21). Females had statistically higher BPA LSGM concentrations than males (p = 0.043). Children had higher concentrations than adolescents (p $45,000/year). Conclusions Urine concentrations of total BPA differed by race/ethnicity, age, sex, and household income. These first U.S. population representative concentration data for urinary BPA and tOP should help guide public health research priorities, including studies of exposure pathways, potential health effects, and risk assessment.

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Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population

Antonia M Calafat, Zsuzsanna Kuklenyik, John A. Reidy … (2004)

Bisphenol A (BPA) is used to manufacture polycarbonate plastic and epoxy resins, which are used in baby bottles, as protective coatings on food containers, and for composites and sealants in dentistry. 4-Nonylphenol (NP) is used to make nonylphenol ethoxylates, nonionic surfactants applied as emulsifying, wetting, dispersing, or stabilizing agents in industrial, agricultural, and domestic consumer products. The potential for human exposure to BPA and NP is high because of their widespread use. We measured BPA and NP in archived urine samples from a reference population of 394 adults in the United States using isotope-dilution gas chromatography/mass spectrometry. The concentration ranges of BPA and NP were similar to those observed in other human populations. BPA was detected in 95% of the samples examined at concentrations ≥0.1 μg/L urine; the geometric mean and median concentrations were 1.33 μg/L (1.36 μg/g creatinine) and 1.28 μg/L (1.32 μg/g creatinine), respectively; the 95th percentile concentration was 5.18 μg/L (7.95 μg/g creatinine). NP was detected in 51% of the samples examined ≥0.1 μg/L. The median and 95th percentile concentrations were < 0.1 μg/L and 1.57 μg/L (1.39 μg/g creatinine), respectively. The frequent detection of BPA suggests widespread exposure to this compound in residents of the United States. The lower frequency of detection of NP than of BPA could be explained by a lower exposure of humans to NP, by different pharmacokinetic factors (i.e., absorption, distribution, metabolism, elimination), by the fact that 4-n-nonylphenol—the measured NP isomer—represents a small percentage of the NP used in commercial mixtures, or a combination of all of the above. Additional research is needed to determine the best urinary biomarker(s) to assess exposure to NP. Despite the sample population’s nonrepresentativeness of the U.S. population (although sample weights were used to improve the extent to which the results represent the U.S. population) and relatively small size, this study provides the first reference range of human internal dose levels of BPA and NP in a demographically diverse human population.

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Several environmental oestrogens are also anti-androgens.

David J. T. Sumpter, P Sohoni (1998)

There is presently considerable interest in endocrine disruption which is a new area of endocrinology concerned with chemicals that mimic hormones, in particular sex steroids. It has been hypothesised that exposure to such chemicals may be responsible for adverse effects in both humans and wildlife. Until now, chemicals that mimic oestrogens (so-called xenoestrogens) have been the main focus of endocrine disruption research. However, recent evidence suggests that many abnormalities in the male reproductive system may be mediated via the androgen receptor. By blocking androgen action, exposure to an anti-androgen may cause changes similar to those associated with oestrogen exposure. We have used in vitro yeast-based assays to detect oestrogenic, anti-oestrogenic, androgenic and anti-androgenic activities in a variety of chemicals of current interest. We show that many of the so-called 'environmental oestrogens' also possess anti-androgenic activity. The previously reported anti-androgenic activities of vinclozolin and p,p'-1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) were confirmed. We also found that o,p'-1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), bisphenol A and butyl benzyl phthalate were anti-androgenic. However, not all xenoestrogens are also anti-androgenic, because nonylphenol was found to be a weak androgen agonist. Our results demonstrate that hormone-mimicking chemicals can have multiple hormonal activities, which may make it difficult to interpret their mechanisms of action in vivo. Although not a specific objective of this study, our results also demonstrate that yeast-based assays are powerful tools with which to investigate both agonist and antagonistic hormonal activities of chemicals.

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Author and article information

Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 02 December 2011

Publication date Collection: December 2011

Volume: 16

Issue: 12

Pages: 9983-10001

Affiliations

[1 ] The 2nd Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang 325000, China

[2 ] Biopharmaceutical Research and Development Center, Jinan University, Guangzhou 510632, China; Email: su_zhijian@ 123456126.com (Z.-J.S.)

[3 ] Population Council and Rockefeller University, 1230 York Avenue, New York, NY 10065, USA

Author notes

[* ] Authors to whom correspondence should be addressed; Email: yeleping@ 123456163.com (L.Y.); rge@ 123456popcbr.rockefeller.edu (R.-S.G.); Tel.: +1-212-327-8754 (R.-S.G.); Fax: +1-212-327-7678 (R.-S.G.).

Article

Publisher ID: molecules-16-09983

DOI: 10.3390/molecules16129983

PMC ID: 6264586

PubMed ID: 22138857

SO-VID: 9d7f3709-c5b7-4251-a731-2c26a65eaf37

License:

licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

History

Date received : 02 November 2011

Date revision received : 21 November 2011

Date accepted : 21 November 2011

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Inhibitors of Testosterone Biosynthetic and Metabolic Activation Enzymes

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Most cited references 119

Exposure of the U.S. Population to Bisphenol A and 4-tertiary-Octylphenol: 2003–2004

Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population

Several environmental oestrogens are also anti-androgens.

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