Effects Of Estrogen On The Expression Of Carboxylesterases In Liver Of Mice

The drugs are regarded as exogenous materials after being taken, which can be metabolized by the liver through the drug metabolizing enzymes. Drug metabolizing enzymes, involved in the metabolism, can be divided into two phases: the phase I drug metabolizing enzymes and the phase II drug metabolizing enzymes. Cytochrome P450 and carboxylesterase belong to the phase I drug metabolizing enzymes, while Sulfotransferase and glutathione S-transferase belong to the phase II drug metabolizing enzymes.Many factors affect the expression and activity of drug metabolizing enzymes, such as physiological factors, environmental factors, diet, disease and medication. The physiological factors include gender, age, race and individual differences. Lots of studies about human and animal models show that gender is an important factor that influences the expression and activity of drug metabolizing enzymes.The enzymes of drug metabolism in pregnant women and postmenopausal women are different from those in normal women and men. It may lead to treatment failure or toxic effects if pregnant or postmenopausal women take the same dose of drugs as normal women. The main reason is that the change of estrogen in pregnant women and postmenopausal women may cause the alteration of metabolizing drugs.Estrogens, including estrone, estradiol and estriol, are important hormones in the body, among which the biological activity of the estradiol is the strongest. First, the estrogens secret into the blood and reache the target tissues. Then, they combined with the membrane or nuclear receptors on target cells to activate the signal transduction pathway. The effects of estradiol on the target tissues are mediated through four pathways: the classical ligand-dependent pathway, ligand-independent transduction pathway, ERE-independent transduction pathway and Cell-surface signaling. 17β-estrogen could change the expression and activity of some kinds of Cytochrome P450. The level of 17β-estrogen in pregnant women is 100 times higher than that in normal women and men. Compared with that of normal women and men, the level of 17β-estrogen in postmenopausal women decreases 80% to 90%. 17β-estrogen can influence the metabolism of drug through the effect on the expression of some drug metabolizing enzymes. The optimal dose of medication for pregnant women and postmenopausal women would change because of the changes in the expression of several drug metabolizing enzymes.Carboxylesterase belongs to the phase I drug metabolizing enzymes. They exist in the microsomes of liver, intestinal and kidney. Carboxylic ester, carboxylamine, amide and thioester can be hydrolyzed by them. Carboxylesterase can be divided into CES1(mouse Ces1d) and CES2(mouse Ces1e). The structures CES1(Ces1d) and CES2(Ces1e) are different, as well as the drugs that they hydrolyzed. ACEI and clopidogrel could be hydrolyzed by CES1(Ces1d). These prodrugs could treat the diseases after they were hydrolyzed. Hypertension is a major cause of cardiovascular disease in older women. Hypertension during gestation period is the main cause of maternal and perinatal death. Irinotecan, an anticancer prodrug, could be hydrolyzed by CES2(Ces1e). Effects of 17β-estradiol on the expression of carboxylesterase were important to the optimal dose of medication for pregnant women and postmenopausal women.Purpose: Effects of estrogen on the expression of carboxylesterases in liver of mice.Methods: We randomly divided thirty female ICR mice into three groups: sham-operated(SHAM), ovariectomized(OVX), and ovariectomy plus estrogen therapy group(OVX+E2). The livers were perfused and isolated when mice were sacrificed. We measured the mRNA, protein levels of Ces1 d, Ces1 e and hydrolytic activity in livers. In vitro, mouse primary hepatocytes were treated with different concentrations of estrogen. We measured the mRNA, protein levels of Ces1 d, Ces1 e and hydrolytic activity of mouse primary hepatocytes in diferent time. Then the mouse primary hepatocytes were pretreated with ActD(the transcription inhibitor) or SP600125(inhibitor of the AP-1 pathway) to explore the mechanism of estrogen to suppression Ces1 d, Ces1 e.Results: 1.In the experiment of animals, the mRNA, protein levels of Ces1 d, Ces1 e and hydrolytic activity in OVX group were higher than those in SHAM or OVX+E2 groups. The mRNA, protein levels of Ces1 d, Ces1 e and hydrolytic activity in OVX+E2 group were lower than those in OVX groups. And they were very close to those in SHAM group. The data suggested that estrogen can decrease the mRNA, protein levels of Ces1 d, Ces1 e and hydrolytic activity in the liver of mice.2. In vitro, estrogen can decrease the mRNA, protein levels and activity of Ces1 d and Ces1 e in primary mouse hepatocytes. 3. The primary mouse hepatocytes, pretreated with ActD before the treatment with estrogen, almost abolished the decreased the mRNA of Ces1 d and Ces1 e, compared with the cells treated with estrogen alone.4. The primary mouse hepatocytes that were pretreated with SP600125 before the treatment with estrogen could alleviate the decreased the mRNA and protein levels of Ces1 d and Ces1 e, compared with the cells treated with estrogen alone.Conclusion: Estrogen negatively regulates the expression of Ces1 d,Ces1e in transcription level through AP-1 pathway.