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 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 through trans-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.
Zhu
W
W
Department of Biomedical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Song
L
L
Zhang
H
H
Matoney
L
L
LeCluyse
E
E
Yan
B
B
D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000918:Antibody Specificity; D015152:Blotting, Northern; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010920:Placenta / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000893:Anti-Inflammatory Agents; D012333:RNA, Messenger; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D002265:Carboxylic Ester Hydrolases; C092264:hydrolase C; D043182:Carboxylesterase