Mini reviewCytochrome P450-mediated metabolism of estrogens and its regulation in human
Introduction
Estrogens exert diverse biological effects such as female sexual differentiation and development, arterial vasodilation, the maintenance of bone density, and neuroprotective actions. Many of these effects result from direct interaction between estrogen and the estrogen receptor (ER), which activates the expression of target genes encoding proteins with important biological functions [1], [2], [3]. One of the most notable effects of estrogens is their contribution to the development and evolution of breast cancer and endometrial cancer [4], [5]. Prolonged exposure to estrogens is considered an important etiological factor for the induction of estrogen-associated cancers [6], [7]. Estrogens are eliminated from the body by metabolic transformation to estrogenically inactive metabolites that are excreted in the urine and/or feces. The metabolism of estrogens includes oxidation (mainly hydroxylation) by cytochrome P450s (CYPs), glucuronidation by UDP-glucuronosyltransferase, sulfation by sulfotransferase, and O-methylation by catechol O-methyltransferase (COMT) [8], [9], [10], [11]. The first step in the metabolism of estrogens, hydroxylation, is mediated by CYP enzymes. CYP consists of a superfamily of heme-containing monooxygenases and is responsible for the oxidative metabolism of many drugs and environmental chemicals as well as endogenous substances including steroids [12]. Three families (CYP1, CYP2, and CYP3) mainly catalyze the oxidative metabolism of exogenous and endogenous compounds. Some isoforms in these CYP families are also responsible for the metabolism of estrogens. The expression level of the estrogen-metabolizing CYP enzymes is regulated by many factors in the liver and target tissues. Therefore, the metabolism of estrogen not only alters the intensity of its action but may also alter the profile of its physiological effects in target tissues. In this mini-review, we discuss the CYP-mediated metabolism of estrogens, the regulation of the estrogen-metabolizing CYP enzymes, and the association with cancer susceptibility.
Section snippets
Biotransformation of estrogens in human
The biosynthesis of estrogens from cholesterol involves a series of enzymatic steps (Fig. 1). CYP11A catalyzes pregnenolone formation from cholesterol. CYP17 catalyzes androgen formation from pregnenolone. CYP19 catalyzes estrogens from androgens. Estrone is converted to potent estradiol by 17β-hydroxysteroid dehydrogenase (17β-HSD) [13]. In pre-menopausal females, ovary and adrenal glands are the principal source of estradiol [14], [15], [16]. In males or post-menopausal females, the ovary
Role of estradiol and its metabolites in carcinogenesis
In animals and humans, elevated circulating estrogen levels increase the risk of breast or endometrial cancer [30]. One postulated mechanism for the carcinogenesis is that estrogens themselves act as a hormone stimulating cell proliferation. The other postulated mechanism is that estrogens act as a procarcinogen that induces genotoxicity. A catechol metabolite, 4-hydroxyestradiol, formed by CYPs generates free radicals from reductive-oxidative cycling with the corresponding semiquinone and
Regulation of CYP enzymes catalyzing estrogen metabolism
CYP1A1, which catalyzes the 2-hydroxylation of estradiol, is induced by numerous polycyclic aromatic hydrocarbons (PAHs) and aryl amines [23] as well as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [48]. This induction is mediated by the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) [48], [49], [50]. The liganded-AhR/ARNT heterodimer interacts with the xenobiotic responsive element (XRE) located in the enhancer region of the target genes, and subsequently transcription of
Genetic polymorphisms of CYP enzymes that catalyze estrogen metabolism and the association with cancer risk
For the human CYP1A1 gene, several variant alleles including CYP1A1*1B to CYP1A1*11 have been identified (http://www.imm.ki.se/CYPalleles/). Among them, CYP1A1*2A giving rise to an Msp I restriction site in the 3′-noncoding region at T3801C and CYP1A1*2C with an amino acid substitution at codon Ile462Val have been reported to significantly elevate the inducible enzymatic activity compared with the wild-type genotype. Some studies reported that CYP1A1*2A and *2C variants increase the risk of
Conclusion
Biotransformation of steroid hormones constitutes a dynamic network of control for the bioavailability of steroid hormones to their corresponding target receptors. The liver is the most important organ for steroid hormone catabolism, and other local organs also contribute to the catabolism. Recently, the concept of intracrinology has become important for the estrogen activity in local tissues [89]. Inactive steroids in plasma are locally converted to bioactive estrogens in the reproductive
Acknowledgements
We acknowledge Mr Brent Bell for reviewing the manuscript.
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