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Vol. 28, Issue 2, 186-191, February 2000
Department of Biomedical Sciences, University of Rhode Island,
Kingston, Rhode Island.
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.
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