Suppression of Hydroxysteroid Sulfotransferase-a Gene Expression by 3-Methylcholanthrene

doi:10.1006/taap.1994.1057

Toxicology and Applied Pharmacology

Volume 125, Issue 1, March 1994, Pages 133-141

https://doi.org/10.1006/taap.1994.1057 Get rights and content

Abstract

The hydroxysteroid sulfotransferases (HSTs) are phase II drug metabolizing enzymes which play a role in xenobiotic detoxication, carcinogen activation, and intratissue hormone modulation. Rat liver contains three principal HST enzymes. Of these, HST-a is most abundant in female rat liver. The phase I drug metabolizing enzyme cytochrome P450 1A1 (CYP1A1) provides a major pathway for polycyclic aromatic hydrocarbon (PAH) carcinogen activation, whereas HST-a, through enzymatic sulfation, offers an alternative pathway for PAH carcinogen activation. Transcription of the rat hepatic CYP1A1 gene is induced in response to treatment with PAH carcinogen 3-methylcholanthrene (3-MC). In view of the potential importance of enzymatic sulfation to the complex process of PAH carcinogenesis, the effect of 3-MC on HST-a gene expression was investigated. Groups of prepubescent (aged ≍22-30 days) and young adult female (aged ≍69-84 days) Sprague-Dawley rats were injected ip with corn oil vehicle or with 3-MC (80 mg/kg). After fasting for 24 hr, rats were terminated and hepatic HST-a gene expression was analyzed using slot blot, Northern blot, and Western blot analyses. Initial Northern blot and slot blot analyses demonstrated a substantial suppression of rat hepatic HST-a mRNA in both prepubescent and young adult female rats. Subsequent Northern blot analyses on liver tissue isolated from female rats aged ≍55 days confirmed CYP1A1 mRNA induction in 3-MC-treated animals and demonstrated a dose-dependent suppression of HST-a mRNA expression of ≍25, 50, and 75% in rats treated with 10, 25, and 80 mg/kg 3-MC ip, respectively. In contrast, HST-a protein levels remained unaltered 24 hr after 3-MC treatment. A time-course study revealed that hepatic HST-a mRNA levels returned to control levels by 36 hr following 3-MC treatment. These results suggest that xenobiotics such as 3-MC modulate HST-a mRNA expression and that HST-a mRNA suppression after 3-MC treatment may occur at the level of transcription.

References (0)

Cited by (32)

Measurement of hair thyroid and steroid hormone concentrations in the rat evidence endocrine disrupting potential of a low dose mixture of polycyclic aromatic hydrocarbons
2022, Environmental Pollution
Citation Excerpt :
Indeed, BaP has been shown to inhibit steroidogenic enzymes in Leydig cells and testis of male rats and in ovary of crab and marine bivalve mollusk, such as P450c17, 3β-HSD and 17β-HSD (Chung et al., 2011; Liang et al., 2012; Reddy et al., 2015; Wen and Pan, 2015; Yang et al., 2020). Likewise, it has been demonstrated that AhR activation can cause suppression of SULT gene expression in MCF10A breast epithelial cells, primary rat hepatocyte culture and rat liver (Runge-Morris and Wilusz, 1994; Runge-Morris, 1998; Fu et al., 2011). PAHs might thus be able to inhibit SULT activity via AhR activation since they are high affinity AhR ligands, which may explain the increased DHEA/DHEAS ratio observed in the present study.
Polycyclic aromatic hydrocarbons (PAHs) have been shown to influence endogenous hormones levels in animal models, but little is known about the effects of their mixtures. For hormone measurements, hair analysis is a promising approach to provide information on long-term status of hormones. Herein we used hair analysis to assess the combined effects of 13 PAHs on steroid and thyroid hormones levels in a rat model. The PAH mixture was administered orally three times per week to female rats at doses of 0, 10, 20, 40, 80, 200, 400 and 800 μg/kg of body weight for each compound over a 90-day exposure period. Fourteen out of 36 analyzed hormones were detected in rat hair, including pregnenolone (P5), 17α-hydroxyprogesterone (17-OHP4), corticosterone (CORT), dehydroepiandrosterone (DHEA), androstenedione (AD), 3,3′-diiodo-L-thyronine (T2), 3,3′,5-triiodo-L-thyronine (T3), and 3,5,3′,5′-triiodo-L-thyronine (T4). The PAH mixture significantly elevated P5 and DHEA levels at the doses of 200 and 400 μg/kg but reduced T2 and T3 levels at the highest dose as compared to the control. While P5, DHEA, 17-OHP4 and AD concentrations exhibited inverted U-shaped dose responses, T2, T3 and T4 concentrations exhibited inverse linear dose responses, which are further confirmed by their relationships with hair hydroxylated PAHs (OH-PAHs) concentrations. Likewise, there were significant nonmonotonic relationships of hormone molar ratios (e.g., AD/17-OHP4 and DHEA/CORT ratios) with exposure intensity and OH-PAHs. Overall, our results demonstrate the capability of PAH mixtures to interfere with steroid and thyroid hormones in female rats.
Sulfotransferases
2018, Comprehensive Toxicology: Third Edition
Sulfotransferases catalyze the formation of sulfuric acid esters, most often referred to as sulfates, from a wide range of xenobiotics and their metabolites, as well as various endogenous neurotransmitters, hormones, bile acids, carbohydrates, and proteins. This article is focused on the cytosolic sulfotransferases, a superfamily of enzymes that, depending on the specific substrates and products of the sulfation reaction, are responsible for either detoxication or metabolic activation of a wide range of drugs, toxins, carcinogens, environmental chemicals, and other xenobiotics. An overview of current aspects of the nomenclature, gene organization, regulation of expression, enzyme structures and catalytic mechanisms, specificities for substrates and inhibitors, and roles in toxicology is provided for these cytosolic sulfotransferases.
Sulfotransferases
2010, Comprehensive Toxicology, Second Edition
Sulfotransferases catalyze the formation of sulfuric acid esters, most often referred to as sulfates, from a wide range of xenobiotics and their metabolites, as well as various endogenous neurotransmitters, hormones, bile acids, carbohydrates, and proteins. This chapter is focused on the cytosolic sulfotransferases, a superfamily of enzymes that, depending on the specific substrates and products of the sulfation reaction, are responsible for either detoxication or metabolic activation of a wide range of drugs, toxins, carcinogens, environmental chemicals, and other xenobiotics. An overview of current aspects of the nomenclature, gene organization, regulation of expression, enzyme structures and catalytic mechanisms, specificities for substrates and inhibitors, and roles in toxicology is provided for these cytosolic sulfotransferases.
Inhibition of liver methionine adenosyltransferase gene expression by 3-methylcolanthrene: Protective effect of S-adenosylmethionine
2001, Biochemical Pharmacology
Citation Excerpt :
These compounds exert profound effects on the expression of a variety of genes, in particular those involved in drug metabolism, the induction of CYP1A1 being among the best-characterized responses [16–18]. In addition to the well-known induction of gene expression by PAHs, these chemicals have also been shown to impair the expression of other genes, such as γ-glutamyltranspeptidase [19] and the drug-metabolizing enzymes cytochrome CYP2C11 [20–24] and hydroxysteroid sulfotransferase-a [25]. However, the molecular mechanisms behind PAH-mediated down-regulation of gene expression are less well understood.
Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the most important biological methyl donor. Liver MAT I/III is the product of the MAT1A gene. Hepatic MAT I/III activity and MAT1A expression are compromised under pathological conditions such as alcoholic liver disease and hepatic cirrhosis, and this gene is silenced upon neoplastic transformation of the liver. In the present work, we evaluated whether MAT1A expression could be targeted by the polycyclic arylhydrocarbon (PAH) 3-methylcholanthrene (3-MC) in rat liver and cultured hepatocytes. MAT1A mRNA levels were reduced by 50% following in vivo administration of 3-MC to adult male rats (100 mg/kg, p.o., 4 days’ treatment). This effect was reproduced in a time- and dose-dependent fashion in cultured rat hepatocytes, and was accompanied by the induction of cytochrome P450 1A1 gene expression. This action of 3-MC was mimicked by other PAHs such as benzo[a]pyrene and benzo[e]pyrene, but not by the model arylhydrocarbon receptor (AhR) activator 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3-MC inhibited transcription driven by a MAT1A promoter–reporter construct transfected into rat hepatocytes, but MAT1A mRNA stability was not affected. We recently showed that liver MAT1A expression is induced by AdoMet in cultured hepatocytes. Here, we observed that exogenously added AdoMet prevented the negative effects of 3-MC on MAT1A expression. Taken together, our data demonstrate that liver MAT1A gene expression is targeted by PAHs, independently of AhR activation. The effect of AdoMet may be part of the protective action of this molecule in liver damage.
Induction of rat hepatic aryl sulfotransferase (SULT1A1) gene expression by triamcinolone acetonide: Impact on minoxidil-mediated hypotension
2000, Toxicology and Applied Pharmacology
The hypotensive agent minoxidil (6-imino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine) depends upon aryl sulfotransferase (SULT1)-catalyzed sulfation for its bioactivation. Previous reports suggest that glucocorticoids induce class-specific SULT1 and isoform-specific SULT1A1 gene expression in rat liver. In the present study, rats were treated with the glucocorticoid triamcinolone acetonide (TA, 5 mg/kg/day ip × 3 days) or its vehicle, 2% Tween-20, prior to minoxidil, and subsequent effects on mean arterial pressure (MAP), heart rate (HR), and hepatic SULT1 gene expression were characterized. Minoxidil treatment (1.5 mg/kg) resulted in a steady decline in MAP values of 16.3 to 18.6% relative to basal control levels at 35 to 60 min following minoxidil injection. Pentachlorophenol (PCP, 40 μmol/kg ip), an inhibitor of SULT1 enzyme activity, effectively ablated the hypotensive effects of minoxidil. By contrast, pretreatment with TA significantly enhanced minoxidil-induced hypotension. Relative to vehicle-treated controls, TA-treated rats displayed a steeper rate of decline in MAP and more profound levels of hypotension with decreases in MAP following minoxidil administration of 27.8%. TA also produced significant increases in hepatic SULT1 mRNA expression (of 271%) and SULT1A1 immunoreactive protein levels (of 273%), relative to vehicle-treated controls. These results provide physiological evidence to support the biological relevance of SULT1A1 induction by glucocorticoids. The data indicate that steroid treatment induces SULT1A1 gene expression and, as a consequence, accentuates the hypotensive effects of minoxidil.
Effect of liquorice and glycyrrhizin on rat liver carcinogen metabolizing enzymes
1999, Cancer Letters
We investigated the effect of single or repeated intake of conspicuous amounts of licorice root extract (LE, 3138 or 6276 mg/kg body weight (bw) per os) or its natural constituent glycyrrhizin (G, 240 or 480 mg/kg bw per os) on Sprague–Dawley rat liver monooxygenases. Whereas a single LE or G dose was unable to affect CYP superfamily, four daily doses induced CYP3A, CYP1A2 and to varying extents CYP2B1-linked monooxygenases. A boosting effect on testosterone 6β- (CYP3A1/2, CYP1A1/2), 7α- (CYP1A1/2, CYP2A1), 16α- (CYP2B1, CYP2C11), 2α- (CYP2C11) and 2β-(CYP3A1, CYP1A1) -dependent oxidases as well as on androst-4-ene-3,17-dione- (CYP3A1/2) -supported monooxygenases were also achieved. Harmful outcomes associated to CYP changes (e.g. cotoxicity, cocarcinogenicity and promotion) may be of concern.

View all citing articles on Scopus

View full text

Regular ArticleSuppression of Hydroxysteroid Sulfotransferase-a Gene Expression by 3-Methylcholanthrene

Abstract

Regular Article
Suppression of Hydroxysteroid Sulfotransferase-a Gene Expression by 3-Methylcholanthrene