Two distinct mechanisms for regulation of gamma-glutamyl transpeptidase in cultured rat hepatocytes by glucocorticoid-like steroids.
Adult rat hepatocytes maintained in primary monolayer culture with defined medium were used to characterise two effects of glucocorticoid-like steroids in regulating gamma-glutamyltranspeptidase (GGT). Low concentrations of glucocorticoids alone had little effect on GGT but synergistically enhanced induction of the enzyme by liver tumor-promoting xenobiotics such as 1,1,1-trichloro-2,2-bis-(4-chlorophenyl)-ethane (DDT) and hexachlorocyclohexane. The enhancing effect appears to be mediated by the classical glucocorticoid hormone receptor since structural requirements and concentration-dependence for enhancement were similar to those for induction of tyrosine aminotransferase in parallel cultures. Higher concentrations (1-100 microM) of various glucocorticoids alone increased GGT activity. Most glucocorticoids induced GGT but their order of potency did not parallel that for induction of tyrosine aminotransferase under similar culture conditions. Among the most potent glucocorticoids, triamcinolone was a weak GGT inducer and cortivazol appeared to act as an antagonist of GGT induction by steroids. Some non-glucocorticoids including pregnenolone 16 alpha-carbonitrile, and some progestins, also induced but required addition of 30 nM dexamethasone for maximal effect. Some specific steroid structural features were identified which increased (presence of a 16 alpha methyl group) or impaired GGT-inducing activity. Although interpretation is complicated by differential metabolism of individual steroids in culture, the results suggest that GGT induction by pharmacological levels of steroids may be mediated, directly or indirectly, by one or more relatively specific receptors distinct from the classical glucocorticoid receptor.
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004963:Estrenes / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014444:Tyrosine Transaminase / Q000096:biosynthesis; D005723:gamma-Glutamyltransferase / Q000032:analysis / Q000096:biosynthesis*
D004963:Estrenes; D005938:Glucocorticoids; D011281:Pregnatrienes; D005723:gamma-Glutamyltransferase; D014444:Tyrosine Transaminase; C005924:cortivazol