Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1998 Feb 20;109(1-3):315-27.
doi: 10.1016/s0009-2797(97)00142-7.

Regulation of Sulfotransferase Gene Expression by Glucocorticoid Hormones and Xenobiotics in Primary Rat Hepatocyte Culture

Affiliations

Regulation of Sulfotransferase Gene Expression by Glucocorticoid Hormones and Xenobiotics in Primary Rat Hepatocyte Culture

M Runge-Morris. Chem Biol Interact. .

Abstract

In the rat liver, hydroxysteroid sulfotransferase-a (HST-a) and aryl sulfotransferase IV (ASTIV) represent two major rat hepatic sulfotransferases that are important to xenobiotic metabolism. Prototypic CYP1A1 and CYP2B/3A inducers regulate rat hepatic sulfotransferase gene expression although not necessarily in a coordinate direction. It has been previously reported that in vivo treatment with CYP1A1 inducer 3-methylcholanthrene (3-MC) suppresses rat hepatic HST-a mRNA expression in a dose-dependent manner. Similarly, HST-a and ASTIV mRNA levels become suppressed or induced, respectively, following in vivo treatment with phenobarbital (PB)-like CYP2B/3A inducers or prototypic CYP3A inducers such as glucocorticoid hormones. In the whole animal, sulfotransferase gene expression is modulated by members of the hypothalamic/pituitary-adrenal gonadal hormone axis. However, studies in primary rat hepatocyte culture suggest that prototypic P450 inducers regulate HST-a and ASTIV gene expression directly at the level of the hepatocyte. Glucocorticoid-mediated sulfotransferase expression was compared with the regulation of tyrosine amino transferase (TAT), a gene that is transcriptionally regulated by ligand bound glucocorticoid receptor. It was found that lower doses of dexamethasone (DEX, 10(-7) M) produced concomitant increases in ASTIV and TAT mRNA expression, whereas HST-a mRNA expression continued to rise as the DEX dose was increased through 10(-5) M. When hepatocytes were co-incubated with DEX and antiglucocorticoid/antiprogestin RU-486, DEX-stimulated HST-a mRNA expression was not significantly inhibited by RU-486, but ASTIV and TAT mRNA expression were inhibited to a similar extent. The results suggested that ASTIV, like TAT, is likely regulated by a classical glucocorticoid receptor mediated mechanism, whereas HST-a is probably regulated by glucocorticoids via an alternative mechanism. In contrast to the positive effects of glucocorticoid hormones, HST-a and ASTIV mRNA expression was negatively regulated by xenobiotics such as PB-like CYP2B/3A inducers or aryl hydrocarbon receptor (AhR) agonist CYP1A1 inducers. Incubation of primary cultured rat hepatocytes with PB or structurally dissimilar PB-like inducers clotrimazole, diphenylhydantoin, heptachlor, gamma-hexachlorocyclohexane or 2,2',4,4',5,5'-hexachlorobiphenyl suppressed HST-a and ASTIV mRNA levels. Also, incubation of primary cultured rat hepatocytes with CYP1A1 inducer beta-naphthoflavone or with archetypic AhR agonist, 2,3,7,8-tetrachloro-p-dioxin (TCDD) markedly suppressed HST-a and ASTIV mRNA expression. These data suggest that the rat HST-a and ASTIV genes are positively regulated by glucocorticoid hormones and negatively regulated by xenobiotics as a result of molecular and cellular mechanisms that act directly on the hepatocyte.

Similar articles

See all similar articles

Cited by 4 articles

Publication types

LinkOut - more resources

Feedback