Hydroxylation and sulfation of sex steroid hormones in inflammatory liver

Sex steroids, also known as gonadal steroids, are oxidized with hydroxylation by cytochrome P450,glucuronidation by UDP-glucuronosyltransferase, sulfation by sulfotransferase, and O-methylation by catechol Omethyltransferase. Thus, it is important to determine the process by which inflammation influences metabolism of gonadal hormones. Therefore, we investigated the mechanism of metabolic enzymes against high physiologic inflammatory response in vivo to study their biochemical properties in liver diseases. In this study, C57BL/6N mice were induced with hepatic inflammation by diethylnitrosamine(DEN) exposure. We observed upregulation of Cyp19a1, Hsd17b1, Cyplal, Sult1e1 in the DEN-treated livers compared to the control-treated livers using real time PCR. Moreover, the increased Cyp19a1 and Hsd17b1 levels support the possibility that estrogen biosynthesis from androgens are accumulated during inflammatory liver diseases. Furthermore, the increased levels of Cyp1a1 and Cyp1b1 in the hydroxylation of estrogen facilitated the conversion of estrogen to 2-or 4-hydroxyestrogen,respectively. In addition, the substantial increase in the Sultlel enzyme levels could lead to sulfate conjugation of hydroxyestrogen. The present information supports the concept that inflammatory response can sequester sulfate conjugates from the endogenous steroid hormones and may suppress binding of sex steroid hormones to their receptors in the whole body.

Suppressed estrogen supply via extra-ovarian progesterone receptor membrane component 1 in menopause

In post-menopausal women,intra-mammary estrogen,which is converted from extra-ovarian estrone(E1),promotes the growth of breast cancer.Since the aromatase inhibitor letrozole does not suppress 17β-estradiol(E2)production from E1,high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy.Progesterone receptor membrane component 1(Pgrmc1)is a non-classical progesterone receptor associated with breast cancer progression.In the present study,we introduced a Pgrmc1 heterozygous knockout(hetero KO)murine model exhibiting low Pgrmc1 expression,and observed estrogen levels and steroidogenic gene expression.Naïve Pgrmc1 hetero KO mice exhibited low estrogen(E2 and E1)levels and low progesterone receptor(PR)expression,compared to wild-type mice.In contrast,Pgrmc1 hetero KO mice that have been ovariectomized(OVX),including letrozole-treated OVX mice(OVX-letrozole),exhibited high estrogen levels and PR expression.Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase(STS).In MCF-7 cell,letrozole suppressed PR expression,but PGRMC1 knockdown increased PR and STS expression.Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited,thereby suggesting a potential therapeutic approach for letrozole resistance.

Sex hormone-binding globulin impedes hepatocellular carcinoma growth via MERTK regulation

Sex hormone-binding globulin(SHBG),a crucial modulator of sex steroids in human blood,regulates androgen bioavailability and homeostasis.1 When androgen or AR signaling is known to be involved in the hepatocellular carcinoma(HCC)and SHBG plays an integral role in regulating the levels of bioavailable androgens,the concern whether SHBG might influence HCC onset or progression by modulating androgen action remains open.