Cytochrome P450-mediated metabolism of estrogens and its regulation in human

doi:10.1016/j.canlet.2004.10.007

Cancer Letters

Volume 227, Issue 2, 28 September 2005, Pages 115-124

https://doi.org/10.1016/j.canlet.2004.10.007 Get rights and content

Abstract

Estrogens are eliminated from the body by metabolic conversion to estrogenically inactive metabolites that are excreted in the urine and/or feces. The first step in the metabolism of estrogens is the hydroxylation catalyzed by cytochrome P450 (CYP) enzymes. Since most CYP isoforms are abundantly expressed in liver, the metabolism of estrogens mainly occurs in the liver. A major metabolite of estradiol, 2-hydroxyestradiol, is mainly catalyzed by CYP1A2 and CYP3A4 in liver, and by CYP1A1 in extrahepatic tissues. However, CYP1B1 which is highly expressed in estrogen target tissues including mammary, ovary, and uterus, specifically catalyzes the 4-hydroxylation of estradiol. Since 4-hydroxyestradiol generates free radicals from the reductive-oxidative cycling with the corresponding semiquinone and quinone forms, which cause cellular damage, the specific and local formation of 4-hydroxyestradiol is important for breast and endometrial carcinogenesis. Changes in the expression level of estrogen-metabolizing CYP isoforms not only alter the intensity of the action of estrogen but may also alter the profile of its physiological effect in liver and target tissues. Generally, many CYP isoforms are induced by the substrates themselves, resulting in enhanced metabolism and elimination from the body. Of particular interest is a novel finding that human CYP1B1 is regulated by estradiol via the estrogen receptor. This fact suggests that the regulation of CYP enzymes involved in estrogen metabolism by estrogen itself would be physiologically significant for the homeostasis of estrogens at local organs. In this mini-review, we discuss the CYP-mediated metabolism of estrogens and the regulation of the estrogen-metabolizing CYP enzymes in relation to the risk of cancer.

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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Mini reviewCytochrome P450-mediated metabolism of estrogens and its regulation in human

Abstract

Introduction

Section snippets

Biotransformation of estrogens in human

Role of estradiol and its metabolites in carcinogenesis

Regulation of CYP enzymes catalyzing estrogen metabolism

Genetic polymorphisms of CYP enzymes that catalyze estrogen metabolism and the association with cancer risk

Conclusion

Acknowledgements

Cell

Pharmacol. Ther.

J. Biol. Chem.

Mutat. Res.

Am. J. Obstet. Gynecol.

Am. J. Clin. Nutr.

J. Biol. Chem.

J. Steroid Biochem.

J. Steroid Biochem.

J. Steroid Biochem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

J. Biol. Chem.

FEBS Lett.

Biophys. Res. Commun.

J. Steroid Biochem. Mol. Biol.

Biophys. Acta

J. Biol. Chem.

A.K. Nussler, P. Neuhaus, M. Eichelbaum, M. Schwab, U.M. Zanger, Sex is a major determinant of CYP3A4 expression in human liver, Hepatology

Gynecol. Oncol.

The steroid and thyroid hormone receptor superfamily

Science

Estrogen stimulates transcription of c-jun protooncogene

Mol. Endocrinol.

Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis

Proc. Natl Acad. Sci. USA

Antiestrogens: clinical applications of pharmacology

J. Soc. Gynecol. Invest.

Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk

Epidemiol. Rev.

Estrogens and breast cancer

Carcinogenesis

Sulfation of estrone and 17β-estradiol in human liver. Catalysis by thermostable phenol sulfotransferase and by dehydroepiandrosterone sulfotransferase

Drug Metab. Dispos.

Catecholoestrogens (2- and 4-hydroxyoestrogens): chemistry, biogenesis, metabolism, occurrence and physiological significance

Acta Endocrinol.

P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature

Pharmacogenetics

Source of estrogen production in postmenopausal women

J. Clin. Endocrinol. Metab.

In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway

J. Clin. Endocrinol. Metab.

Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human adult and fetal tissues

J. Clin. Endocrinol. Metab.

Characterization of the NADPH-dependent metabolism of 17β-estradiol to multiple metabolites by human liver microsomes and selectively expressed human cytochrome P450 3A4 and 3A5

J. Pharmacol. Exp. Ther.

NADPH-dependent metabolism of estrone by human liver microsomes

J. Pharmacol. Exp. Ther.

Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens

Endocrinology

Characterization of the oxidative metabolites of 17β-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms

Endocrinology

Oxidation of 17α-ethynylestradiol by human liver cytochrome P-450

Mol. Pharmacol.

Estradiol metabolism by complementary deoxyribonucleic acid-expressed human cytochrome P450s

Endocrinology

Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone

Carcinogenesis

4-Hydroxylation of estradiol by human uterine myometrium and myoma microsomes: implications for the mechanism of uterine tumorigenesis

Proc. Natl Acad. Sci. USA

4-Hydroxylation of estrogens as marker of human mammary tumors

Proc. Natl Acad. Sci. USA

Formation of 2- and 4-hydroxyestrogens by brain, pituitary, and liver of the human fetus

J. Clin. Endocrinol. Metab.

17β-Estradiol hydroxylation catalyzed by human cytochrome P450 1B1

Proc. Natl Acad. Sci. USA

Mini review
Cytochrome P450-mediated metabolism of estrogens and its regulation in human