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Differential effects of 17α-ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat

Author: Koopen, N.R. · Post, S.M. · Wolters, H. · Havinga, R. · Stellaard, F. · Boverhof, R. · Kuipers, F. · Princen, H.M.G.
Institution: Gaubius instituut TNO
Source:Journal of Lipid Research, 1, 40, 100-108
Identifier: 280457
Keywords: Δ-<sup>22</sup>-β-muricholate · Bile · Cholestasis · Cholesterol-7α- hydroxylase · Enterohepatic circulation · Estrogens · Sterol-27-hydroxylase · Wistar rat · Animals · Aryl Hydrocarbon Hydroxylases · Bile Acids and Salts · Chenodeoxycholic Acid · Cholates · Cholesterol 7-alpha-Hydroxylase · Cytochrome P-450 CYP27A1 · Cytochrome P-450 Enzyme System · Enterohepatic Circulation · Ethinyl Estradiol · Hydrogen-Ion Concentration · Liver · Male · Rats · Rats, Wistar · RNA, Messenger · Steroid 12-alpha-Hydroxylase · Steroid Hydroxylases


Effects of 17α-ethinylestradiol (EE) on the neutral and acidic biosynthetic pathways of bile salt (BS) synthesis were evaluated in rats with an intact enterohepatic circulation and in rats with long-term bile diversion to induce BS synthesis. For this purpose, bile salt pool composition, synthesis of individual BS in vivo, hepatic activities, and expression levels of cholesterol 7α-hydroxylase (CYP7A), and sterol 27-hydroxylase (CYP27), as well as of other enzymes involved in BS synthesis, were analyzed in rats treated with EE (5 mg/kg, 3 days) or its vehicle. BS pool size was decreased by 27% but total BS synthesis was not affected by EE in intact rats. Synthesis of cholate was reduced by 68% in EE-treated rats, while that of chenodeoxycholate was increased by 60%. The recently identified Δ<sup>22</sup>- isomer of β-muricholate contributed for 5.4% and 18.3% (P < 0.01) to the pool in control and EE-treated rats, respectively, but could not be detected in bile after exhaustion of the pool. A clear reduction of BS synthesis was found in bile-diverted rats treated with EE, yet biliary BS composition was only minimally affected. Activity of CYP7A was decreased by EE in both intact and bile-diverted rats, whereas the activity of the CYP27 was not affected. Hepatic mRNA levels of CYP7A were significantly reduced by EE in bile- diverted rats only; CYP27 mRNA levels were not affected by EE. In addition, mRNA levels of sterol 12α-hydroxylase and lithocholate 6β-hydroxylase were increased by bile diversion and suppressed by EE. This study shows that 17α- ethinylestradioI (EE)-induced intrahepatic cholestasis in rats is associated with selective inhibition of the neutral pathway of bile salt (BS) synthesis. Simultaneous impairment of other enzymes in the BS biosynthetic pathways may contribute to overall effects of EE on BS synthesis.