Regulation of mouse liver microsomal esterases by clofibrate and sexual hormones

doi:10.1016/S0006-2952(95)02254-6

Biochemical Pharmacology

Volume 51, Issue 5, 8 March 1996, Pages 677-685

https://doi.org/10.1016/S0006-2952(95)02254-6 Get rights and content

Abstract

Carboxylesterase activity was measured using six different substrates in microsomal preparations from female and c-variectomized female mice in order to evaluate the effects of female sex hormones on esterase expression. With three of the substrates (α-naphthyl acetate and esters 2 and 3), esterase activity was the same in both groups; however, with the others (p-nitrophenyl acetate and esters 1 and 4), there was a small increase in activity in ovariectomized females, compared with intact females. Castration of males followed by treatment with testosterone caused only transient increases in activity for four of the substrates (α-naphthyl acetate and esters 1, 2, and 3) and no change in activity for the other two (p-nitrophenyl acetate and ester 4). Treatment of male and female mice with the peroxisome proliferator clofibrate, with or without testosterone, resulted in increased hydrolysis of α-naphthyl acetate and p-nitrophenyl acetate, but little change for the other substrates. Clofibrate also induced α-naphthyl acetate and p-nitrophenyl acetate hydrolysis in castrated males, but clofibrate and testosterone administered together resulted in significant increases of activity with all substrates, which were greater than the additive effects of the two compounds administered separately. These results indicate that clofibrate causes significant alterations in the regulation of esterase activity, whereas sex hormones only cause small changes. However, it would seem that testosterone can synergize the effect of clofibrate in castrated males, resulting in higher levels of activity than with clofibrate alone. Finally, an overall increase in esterase activity might be due to a large increase in the activity of a few esterases or to a small increase in many esterases. Enzyme staining of native polyacrylamide gels reveals that the latter is true, with the majority of esterases present in mouse liver microsomes being induced to a small degree by clofibrate.

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The nonspecific carboxylesterases (EC.3.1.1.1) are a large group of enzymes that play important roles in the metabolism of foreign xenobiotics and endogenous lipids, including activators of the peroxisome proliferator-activated receptor α, a nuclear receptor that is the central mediator of peroxisome proliferator (PP) effects in the rodent liver. A number of reports have demonstrated that PP exposure leads to alterations in levels of carboxylesterases in the liver. In this study, we determined by Western blot analysis whether exposure to diverse PP results in alteration of expression of two highly expressed microsomal carboxylesterases. Chronic exposure to the PP WY-14,643 (WY) and gemfibrozil (GEM), but not di-n-butyl phthalate (DBP), led to decreases in ES-4 in male rat livers. ES-4 was increased in female rat livers treated with GEM. WY exposure led to decreases in ES-10 in male and female rat livers. ES-10 was increased in female rats treated with DBP. Compared with other end points that are altered within days after PP exposure, the downregulation of ES-4 and ES-10 by WY was considerably slower, occurring between 1 and 5 weeks of exposure. Decreased expression of ES-4 was observed at doses of WY or GEM as low as 10 or 8000 ppm, respectively, whereas decreased expression of ES-10 was more resistant to changes by any PP occurring only with WY at doses as low as 50 ppm. After chronic exposure to WY or diethylhexyl phthalate in wild-type mice, kidney, but not liver, expression of ES-4 and ES-10 was downregulated. These decreases in kidney ES expression were not observed in PPARα-null mice lacking a functional PPARα gene, demonstrating the importance of this transcription factor in these changes. These studies demonstrate that ES protein expression is under complex control by PP that is sex- and compound-dependent. These results lend support to the hypothesis that PP exposure leads to a reprogramming of expression of enzymes important in the metabolism of PPARα activators.
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^☆: This work was supported by Grant RO1 ES02710 from NIEHS. U.C. Davis is an NIEHS Center for Environmental Health Sciences (P30 ES05707) and an EPA Center for Ecological Health Research (CR819658-010).

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Research paperRegulation of mouse liver microsomal esterases by clofibrate and sexual hormones☆

Abstract

Biochem Pharmacol

Toxicol Appl Pharmacol

Food Chem Toxicol

Trends Pharmacol Sci

Arch Biochem Biophys

Biochim Biophys Acta

J Biol Chem

Metabolism

Biochem Pharmacol

Arch Biochem Biophys

Biochem Pharmacol

Biochem Pharmacol

Anal Biochem

Mol Cell Endocrinol

J Biol Chem

Cell

Biochem Pharmacol

The carboxylesterases/amidases of mammalian liver and their possible significance

CRC Crit Rev Toxicol

Role of carboxylesterases in xenobiotic metabolism

Revi Biochem Toxicol

Possible physiological roles of carboxylic ester hydrolases

Drug Metab Rev

Research paper
Regulation of mouse liver microsomal esterases by clofibrate and sexual hormones☆