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Carboxylesterases play an important role in the metabolism of endogenous lipids and foreign compounds; therefore, xenobiotic regulation of carboxylesterase gene expression has both physiological and pharmacological significance. We previously reported that beta-naphthoflavone and 3-methylcholanthrene, two potent inducers for cytochrome P4501A enzymes, had opposing effects on the expression of hydrolase S, a secretory carboxylesterase. Beta-naphthoflavone caused suppression, whereas 3-methylcholanthrene caused induction of the expression of this enzyme. The aim of the present study was to determine the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), another prototypical cytochrome P4501A inducer, on the expression of this and several other rat carboxylesterases (hydrolases A, B, and C) in liver and extrahepatic tissues. Rats received TCDD treatment at nonlethal (&lt;or=10 microg/kg), sublethal (30 microg/kg), or lethal doses (90 microg/kg). The overall hydrolytic activity in the liver microsomes toward both 1-naphthyl- and para-nitrophenylacetate was markedly increased in the nonlethal dosage groups, but markedly decreased in the lethal dosage group. Consistent with such a biphasic dose-response relationship, the levels of enzyme proteins exhibited an initial increase, followed by a decrease in response to nonlethal and lethal doses, respectively. In contrast, treatment with TCDD caused a dose-dependent decrease on the levels of mRNA encoding these enzymes. All liver carboxylesterases showed a similar pattern of change on activity, protein, and mRNA levels, suggesting that TCDD coregulates the expression of these genes. In the extrahepatic tissues, a similar biphasic change was observed in activity and in protein and mRNA levels. In both liver and kidney, the expression of cytochrome P4501A1 (CYP1A1) was significantly induced in a dose-dependent manner. TCDD is known to upregulate the expression of CYP1A1 gene through the aryl hydrocarbon receptor (AhR). The differential effects on the expression of liver carboxylesterases and CYP1A1 suggest that TCDD regulates the expression of hydrolytic enzymes via a mechanism(s) other than the AhR-mediated transcription activation, as observed in the CYP1A1 regulation. The different patterns of change on protein and mRNA levels in the nonlethal dosage groups suggest that TCDD regulates the expression of hepatic carboxylesterases by acting on both transcription and translation.

toxicological sciences

Regulation of Rat Carboxylesterase Expression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD): A Dose-Dependent Decrease in mRNA Levels but a Biphasic Change in Protein Levels and Activity