Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes

doi:10.1016/j.cbi.2004.01.006

Chemico-Biological Interactions

Volume 147, Issue 3, 15 April 2004, Pages 233-246

https://doi.org/10.1016/j.cbi.2004.01.006 Get rights and content

Abstract

Normal reproductive development depends on the interplay of steroid hormones with their receptors at specific tissue sites. The concentrations of hormone ligands in the circulation and at target sites are maintained through coordinated regulation on steroid biosynthesis and degradation. Changed bioavailability of steroids, through alteration of steroidogenesis or biotransformation rates, leads to changes in endocrine function. Steroid hormones lose their receptor reactivity in most cases when they are bound to binding proteins, while metabolic conversion can result in either active or inactive metabolites. Hydroxylation by cytochrome P450 (CYP) enzymes and conjugation with glucuronide and sulfate are among the major hepatic pathways of steroid inactivation. The expression of these biotransformation enzymes can be induced by many xenobiotics. The barbiturate phenobarbital and the environmental toxicant 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are among the well characterized inducers for the CYP 2B and 3A enzymes and selected conjugation enzymes. The induction of the steroid biotransformation enzymes is partly mediated through the activation of a group of nuclear receptors including the glucocorticoid receptor, the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the peroxisome proliferator activated receptors (PPAR). Drug or chemical-induced increases in hepatic enzyme activities are often a basis for drug–drug interactions that lead to enhanced elimination and reduced therapeutic efficacy of steroidal drugs. The effects of enzyme induction on endogenous steroid clearance, along with its possible consequence, are less well understood. While enzyme induction by xenobiotics may increase clearance of the endogenous steroid, regulatory mechanisms for steroid homeostasis may adapt and compensate for altered clearance.

Introduction

Steroid hormones are a large class of lipophilic small molecules that are synthesized in steroidogenic tissues and act on target sites to regulate a myriad of physiological functions. Sexual and reproductive development is closely regulated by androgens, estrogens, and progesterone. Interactions between steroid hormones and their receptors represent many potential sites for xenobiotics to affect adversely normal physiological processes (Fig. 1). While receptor-mediated effects have thus far been most extensively studied as targets for xenobiotic endocrine modulation, altered bioavailability of ligands could also contribute to the overall endocrine effects of these compounds. Presentation of steroid hormones at the target site is achieved not only through biosynthesis and transport, but also through well-coordinated metabolism. Inactivation of steroid hormones can be the result of either enhanced metabolism or increased binding to specific serum proteins [1], [2]. Exposure to exogenous compounds that causes alterations in the biosynthesis or inactivation of endogenous steroids may affect the bioavailability of steroid hormones. This short review examines some common factors regulating bioavailability of steroid hormones, especially the role of inducible hepatic enzymes.

Section snippets

Steroid origins and targets

The core structure of steroids is the cyclopentanoperhydrophenanthrene four-ring hydrocarbon nucleus (steroid nucleus) (Fig. 2). There are two categories of steroids: the gonads and adrenal gland synthesize steroids with intact steroid nucleus, whereas the skin produces Vitamin D and its metabolites that have a broken steroid nucleus. The scope of this article is limited to the first category of steroid.

All steroids are derived from cholesterol. Steroid hormones are produced by the adrenal

5α-Reductase

The basis of steroid metabolic conversion in extrahepatic tissues is cell type-specific expression of the converting enzymes, often at the target tissue sites. Testosterone is metabolized to DHT in the male reproductive tract and in the skin by locally expressed 5α-reductase. While both testosterone and DHT activate the same androgen receptor, the two androgens play distinctively different functional roles. During early development, testosterone is responsible for virilization of the Wolffian

Steroid binding proteins

Steroids entering the blood circulation rapidly reach equilibrium among different body fluid compartments [23]. Protein binding of steroids, along with their enzymatic conversion, regulates the availability of free and biologically active steroids at local target sites. One role of the steroid binding proteins is to transport steroid hormones through the circulation. Both protein-bound and conjugated steroids are generally inactive towards the nuclear steroid hormone receptors. Protein binding

Steroid inactivation

The liver is the most important organ of steroid hormone catabolism. Other organs, including the skin, may also contribute to the catabolism of steroids. While steroid metabolism does not always reduce the biological activities of the hormones, metabolic conversion generally renders steroids inactive. The lipophilic steroid molecules are eliminated from the cells through an array of enzymatic reactions followed by transport across the cellular membrane. Several categories of reaction occurring

Perspective on consequences of modulation on steroid metabolizing enzymes

Induction of hepatic enzymes responsible for steroid oxidative hydroxylation and conjugation will result in higher rate of steroid metabolism and inactivation. Enhanced overall clearance of steroid metabolites, however, may also depend on other factors including cross-membrane transportation, plasma protein binding, and enterohepatic circulation. Little is known regarding how the various mechanisms controlling steroid bioavailability are coordinated at the organism level. Clearly, the classical

Acknowledgements

This work is supported by funds from the Long-Range Research Initiative of the American Chemistry Council.

References (98)

D.J Waxman
Interaction of hepatic cytochromes P-450 with steroid hormones
Biochem. Pharmacol.
(1988)
N.A Compagnone et al.
Neurosteroids: biosynthesis and function of these novel neuromodulators
Front. Neurosci.
(2000)
D.J Mangelsdorf et al.
The nuclear receptor superfamily: the second decade
Cell
(1995)
L Mauriac et al.
Fulvestrant (Faslodex) versus anastrozole for the second-line treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and non-visceral metastases: combined results from two multicentre trials
Eur. J. Cancer
(2003)
L You et al.
Induction of hepatic aromatase by p,p′-DDE in adult male rats
Mol. Cell. Endocrinol.
(2001)
L You et al.
Impaired male sexual development in perinatal Sprague–Dawley and Long–Evans hooded rats exposed in utero and lactationally to p,p′-DDE
Toxicol. Sci.
(1998)
A Billich et al.
Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors
J. Steroid Biochem. Mol. Biol.
(2000)
M Runge-Morris et al.
Age and gender-related gene expression of hydroxysteroid sulfotransferase-a in rat liver
Biochem. Biophys. Res. Commun.
(1991)
C.S Song et al.
Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter
J. Biol. Chem.
(1998)
C.S Song et al.
Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor
J. Biol. Chem.
(2001)

A.C Layton et al.

In vitro estrogen receptor binding of PCBs: measured activity and detection of hydroxylated metabolites in a recombinant yeast assay

Toxicol. Appl. Pharmacol.

(2002)

M Ciotti et al.

Altered coding for a strictly conserved di-glycine in the major bilirubin UDP-glucuronosyltransferase of a Crigler-Najjar type I patient

J. Biol. Chem.

(1995)

M Beaulieu et al.

Isolation and characterization of a novel cDNA encoding a human UDP-glucuronosyltransferase active on C19 steroids

J. Biol. Chem.

(1996)

D.W Hum et al.

Characterization of UDP-glucuronosyltransferases active on steroid hormones

J. Steroid Biochem. Mol. Biol.

(1999)

A Belanger et al.

Characterization and regulation of UDP-glucuronosyltransferases in steroid target tissues

J. Steroid Biochem. Mol. Biol.

(1998)

E Levesque et al.

Effect of fibroblastic growth factors (FGF) on steroid UDP-glucuronosyltransferase expression and activity in the LNCaP cell line

J. Steroid Biochem. Mol. Biol.

(1998)

K Grancharov et al.

Natural and synthetic inhibitors of UDP-glucuronosyltransferase

Pharmacol Ther.

(2001)

M.P Arlotto et al.

Measurement of steroid hydroxylation reactions by high-performance liquid chromatography as indicator of P450 identity and function

Methods Enzymol.

(1991)

D.J Waxman et al.

Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 beta-hydroxylase cytochrome P-450 enzyme

Arch. Biochem. Biophys.

(1988)

M Shibuya et al.

Reduced urinary 6beta-hydroxycortisol to cortisol ratios in patients with liver cirrhosis

Hepatol. Res.

(2003)

L You et al.

Modulations of testosterone-metabolizing cytochrome P-450 enzymes in developing Sprague–Dawley rats following in utero exposure to p,p′-DDE

Toxicol. Appl. Pharmacol.

(1999)

S.A Kliewer et al.

An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

Cell

(1998)

I Tzameli et al.

Role reversal: new insights from new ligands for the xenobiotic receptor CAR

Trends Endocrinol. Metab.

(2001)

H Zhang et al.

Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation

Arch. Biochem. Biophys.

(1999)

L.B Moore et al.

Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands

J. Biol. Chem.

(2000)

R.H Fishman et al.

Long-lasting effects of early barbiturates on central nervous system and behavior

Neurosci. Biobehav. Rev.

(1983)

C.J Henderson et al.

Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase

J. Biol. Chem.

(2003)

B.R Witt et al.

Reproductive steroid hormones: generation, degradation, reception, and action

Clin. Obstet. Gynecol.

(1990)

S. Solomon, The primate placenta as an endocrine organ, in: E. Knobil, J.D. Neill (Eds.), The Physiology of...

R.J. Auchus, W.L. Miller, The principles, pathways, and enzymes of human steroidogenesis, in: L.J. DeGroot, J.L....

L You et al.

Androgen receptor expression in the testes and epididymides of prenatal and postnatal Sprague–Dawley rats

Endocrine

(1998)

A.C.B Cato et al.

Rapid actions of steroid receptors in cellular signaling pathways

Sci. STKE

(2002)

E Falkenstein et al.

Multiple actions of steroid hormones—a focus on rapid, nongenomic effects

Pharmacol. Rev.

(2000)

R.M Evans

The steroid and thyroid hormone receptor superfamily

Science

(1988)

K. Parker, Sexual differentiation, in: J.E. Griffin, S.R. Ojeda (Eds.), Textbook of Endocrine Physiology, 4th ed.,...

R.L. Meisel, B.D. Sachs, The physiology of male sexual behavior, in: E. Knobil, J.D. Neill (Eds.), The Physiology of...

R.J Santen et al.

International Congress on Hormonal Steroids and Hormones and Cancer: adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention

Endocr. Relat. Cancer

(2003)

J.C O’Connor et al.

Detection of the environmental antiandrogen p,p′-DDE in CD and Long–Evans rats using a tier I screening battery and a Hershberger assay

Toxicol. Sci.

(1999)

W.R Kelce et al.

Persistent DDT metabolite p,p′-DDE is a potent androgen receptor antagonist

Nature

(1995)

S.S.C Yen

Dehydroepiandrosterone sulfate and longevity: new clues for an old friend

Proc. Natl. Acad. Sci. U.S.A.

(2001)

M Racchi et al.

Dehydroepiandrosterone (DHEA) and the aging brain: flipping a coin in the “fountain of youth”

CNS Drug Rev.

(2003)

P Vihko et al.

17β-Hydroxysteroid dehydrogenases and cancers

J. Steroid Biochem. Mol. Biol.

(2003)

J.R Seckl et al.

11Beta-hydroxysteroid dehydrogenases: a novel control of glucocorticoid action in the brain

Endocr. Rev.

(2002)

C Wang et al.

Salivary testosterone in men. Further evidence of a direct correlation with free serum testosterone

J. Clin. Endocrinol. Metab.

(1981)

M.C. Luke, D.S. Coffey, The male sex accessory tissues. Structure, androgen action, and physiology, in: E. Knobil, J.D....

G.F. Weinbauer, J. Gromoll, M. Simoni, E. Nieschlag, Physiology of testicular function, in: E. Nieschlag, H.M. Behre...

M.E Baker et al.

Flavonoids inhibit estrogen binding to rat alpha-fetoprotein

Proc. Soc. Exp. Biol. Med.

(1998)

B.J Germain et al.

Role of the serum estrogen-binding protein in the control of tissue estradiol levels during postnatal development of the female rat

Endocrinology

(1978)

M.R Kim et al.

Serum prostate specific antigen

Clin. Endocrinol. (Oxford)

(1999)

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MinireviewSteroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes

Abstract

Introduction

Section snippets

Steroid origins and targets

5α-Reductase

Steroid binding proteins

Steroid inactivation

Perspective on consequences of modulation on steroid metabolizing enzymes

Acknowledgements

Biochem. Pharmacol.

Front. Neurosci.

Cell

Eur. J. Cancer

Mol. Cell. Endocrinol.

Toxicol. Sci.

J. Steroid Biochem. Mol. Biol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

Pharmacol Ther.

Methods Enzymol.

Arch. Biochem. Biophys.

Hepatol. Res.

Toxicol. Appl. Pharmacol.

Cell

Trends Endocrinol. Metab.

Arch. Biochem. Biophys.

J. Biol. Chem.

Neurosci. Biobehav. Rev.

J. Biol. Chem.

Reproductive steroid hormones: generation, degradation, reception, and action

Clin. Obstet. Gynecol.

Androgen receptor expression in the testes and epididymides of prenatal and postnatal Sprague–Dawley rats

Endocrine

Rapid actions of steroid receptors in cellular signaling pathways

Sci. STKE

Multiple actions of steroid hormones—a focus on rapid, nongenomic effects

Pharmacol. Rev.

The steroid and thyroid hormone receptor superfamily

Science

International Congress on Hormonal Steroids and Hormones and Cancer: adaptive hypersensitivity to estrogen: mechanism for superiority of aromatase inhibitors over selective estrogen receptor modulators for breast cancer treatment and prevention

Endocr. Relat. Cancer

Detection of the environmental antiandrogen p,p′-DDE in CD and Long–Evans rats using a tier I screening battery and a Hershberger assay

Toxicol. Sci.

Persistent DDT metabolite p,p′-DDE is a potent androgen receptor antagonist

Nature

Dehydroepiandrosterone sulfate and longevity: new clues for an old friend

Proc. Natl. Acad. Sci. U.S.A.

Dehydroepiandrosterone (DHEA) and the aging brain: flipping a coin in the “fountain of youth”

CNS Drug Rev.

17β-Hydroxysteroid dehydrogenases and cancers

J. Steroid Biochem. Mol. Biol.

11Beta-hydroxysteroid dehydrogenases: a novel control of glucocorticoid action in the brain

Endocr. Rev.

Salivary testosterone in men. Further evidence of a direct correlation with free serum testosterone

J. Clin. Endocrinol. Metab.

Flavonoids inhibit estrogen binding to rat alpha-fetoprotein

Proc. Soc. Exp. Biol. Med.

Role of the serum estrogen-binding protein in the control of tissue estradiol levels during postnatal development of the female rat

Endocrinology

Serum prostate specific antigen

Clin. Endocrinol. (Oxford)

Minireview
Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes