Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats

Carboxylesterases play important roles in the metabolism of endogenous and foreign compounds, therefore, xenobiotic regulation of carboxylesterase gen e expression has both physiological and pharmacological significance. We pr eviously reported that liver microsomal esterase activity was significantly decreased in rats treated with dexamethasone accompanied by a decrease in immunoreactive proteins of rat hydrolase A, B, and C. The aim of this study was to determine whether the suppressed expression of these enzymes was li nked to the change of the mRNA levels, and whether cultured hepatocytes res ponded similar to whole animals to this chemical. Northern blotting analyse s demonstrated that the levels of the corresponding mRNA were markedly decr eased in rats treated with dexamethasone, suggesting that the suppressed ex pression is achieved through trans-suppression and/or increased degradation of the transcripts. Exposure of cultured rat hepatocytes to nanomolar leve ls of dexamethasone markedly decreased the levels of immunoreactive protein s of hydrolase A, B, and C. In contrast, exposure of cultured human hepatoc ytes to dexamethasone caused a slight increase in HCE-1 and HCE-2, two majo r forms of human liver microsomal carboxylesterases. The inductive effects in human hepatocytes were observed only when micromolar concentrations of d examethasone were used. These results suggest that a major species differen ce exists regarding the regulation of carboxylesterase gene expression by d examethasone. Both the glucocorticoid receptor and the pregnane X receptor are known to mediate dexamethasone action. Differential concentrations requ ired suggest that suppression of rat hydrolases is mediated by the glucocor ticoid receptor, whereas the induction of human carboxylesterases is mediat ed by the pregnane X receptor.