17β-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes.

In order to study the influence of estrogen on carboxylesterases, we investigated the effects of 17β-estradiol on CES1 (Ces1d) and CES2 (Ces1e) in human and mouse hepatocytes. After being treated with 17β-estradiol, the mRNA levels of CES1 and CES2 decreased by 29-39% and 28-55%, respectively, in the human hepatocytes from four donors. Consistently, the hydrolysis of para-nitrophenylacetate decreased markedly by 32% induced by 17β-estradiol. Moreover, 17β-estradiol decreased CES1 and CES2 by 45% and 47% respectively at protein levels. The response of altered expression of Ces1d (CES1) and Ces1e (CES2) to 17β-estradiolin in mouse hepatocytes was very similar to that in the human hepatocytes. Further, the decreased Ces1d and Ces1e expression induced by 17β-estradiol could be abolished by SP600125, an inhibitor of AP-1, both at mRNA and protein levels. Likewise, the increased c-Jun expression induced by 17β-estradiol could almost be abolished by SP600125. In vivo, the expression of Ces1d, Ces1e and the hydrolytic activity of liver were higher in the ovariectomized female mice(OVX) than those in control mice(SHAM). However, when 17β-estradiol was administrated, the expression of Ces1d, Ces1e and the hydrolytic activity of liver in the ovariectomized female mice (OVX+E2) became restored to their normal levels. Taken together, 17β-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes. The findings can offer the potential gains in the safety and efficacy of pharmacotherapy for women, especially for pregnant and menopausal women.