RT Journal Article
SR Electronic
T1 Dexamethasone Differentially Regulates Expression of Carboxylesterase Genes in Humans and Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 186
OP 191
VO 28
IS 2
A1 Weizhu Zhu
A1 Li Song
A1 He Zhang
A1 Lynn Matoney
A1 Edward LeCluyse
A1 Bingfang Yan
YR 2000
UL http://dmd.aspetjournals.org/content/28/2/186.abstract
AB Carboxylesterases play important roles in the metabolism of endogenous and foreign compounds, therefore, xenobiotic regulation of carboxylesterase gene expression has both physiological and pharmacological significance. We previously 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 linked to the change of the mRNA levels, and whether cultured hepatocytes responded similar to whole animals to this chemical. Northern blotting analyses demonstrated that the levels of the corresponding mRNA were markedly decreased in rats treated with dexamethasone, suggesting that the suppressed expression is achieved throughtrans-suppression and/or increased degradation of the transcripts. Exposure of cultured rat hepatocytes to nanomolar levels of dexamethasone markedly decreased the levels of immunoreactive proteins of hydrolase A, B, and C. In contrast, exposure of cultured human hepatocytes to dexamethasone caused a slight increase in HCE-1 and HCE-2, two major forms of human liver microsomal carboxylesterases. The inductive effects in human hepatocytes were observed only when micromolar concentrations of dexamethasone were used. These results suggest that a major species difference exists regarding the regulation of carboxylesterase gene expression by dexamethasone. Both the glucocorticoid receptor and the pregnane X receptor are known to mediate dexamethasone action. Differential concentrations required suggest that suppression of rat hydrolases is mediated by the glucocorticoid receptor, whereas the induction of human carboxylesterases is mediated by the pregnane X receptor. The American Society for Pharmacology and Experimental Therapeutics