Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity.
Estrogens are known to cause hepatotoxicity such as intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal replacement therapy. Enterohepatic nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive active/androstane receptor (CAR) are important in maintaining bile acid homeostasis and protecting the liver from bile acid toxicity. However, no nuclear receptor has been implicated in the mechanism for estrogen-induced hepatotoxicity. Here Era(-/-), Erb(-/-), Fxr(-/-), Pxr(-/-), and Car(-/-) mice were employed to show that Era(-/-) mice were resistant to synthetic estrogen 17alpha-ethynylestradiol (EE2)-induced hepatotoxicity as indicated by the fact that the EE2-treated Era(-/-) mice developed none of the hepatotoxic phenotypes such as hepatomegaly, elevation in serum bile acids, increase of alkaline phosphatase activity, liver degeneration, and inflammation. Upon EE2 treatment, estrogen receptor alpha (ERalpha) repressed the expression of bile acid and cholesterol transporters (bile salt export pump (BSEP), Na(+)/taurocholate cotransporting polypeptide (NTCP), OATP1, OATP2, ABCG5, and ABCG8) in the liver. Consistently, biliary secretions of both bile acids and cholesterol were markedly decreased in EE2-treated wild-type mice but not in the EE2-treated Era(-/-) mice. In addition, ERalpha up-regulated the expression of CYP7B1 and down-regulated the CYP7A1 and CYP8B1, shifting bile acid synthesis toward the acidic pathway to increase the serum level of beta-muricholic acid. ERbeta, FXR, PXR, and CAR were not involved in regulating the expression of bile acid transporter and biosynthesis enzyme genes following EE2 exposure. Taken together, these results suggest that ERalpha-mediated repression of hepatic transporters and alterations of bile acid biosynthesis may contribute to development of the EE2-induced hepatotoxicity.
Yamamoto
Yukio
Y
Laboratories of Reproductive and Developmental Toxicology, NIEHS/National Institutes of Health, Research Triangle Park, NC 27709, USA.
Moore
Rick
R
Hess
Holly A
HA
Guo
Grace L
GL
Gonzalez
Frank J
FJ
Korach
Kenneth S
KS
Maronpot
Robert R
RR
Negishi
Masahiko
M
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D004997:Ethinyl Estradiol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological
D001647:Bile Acids and Salts; D047628:Estrogen Receptor alpha; D008055:Lipids; D004997:Ethinyl Estradiol; D002784:Cholesterol