title: Differential effects of 17alpha-ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat.
abstract: Effects of 17alpha-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 7alpha-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 Delta22-isomer of beta-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 12alpha-hydroxylase and lithocholate 6beta-hydroxylase were increased by bile diversion and suppressed by EE. This study shows that 17alpha-ethinylestradiol (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.
authors.affiliation: Groningen Institute for Drug Studies (GIDS), Leiden, The Netherlands.
authors.forename: N R
authors.initials: NR
authors.lastname: Koopen
authors.forename: S M
authors.initials: SM
authors.lastname: Post
authors.forename: H
authors.initials: H
authors.lastname: Wolters
authors.forename: R
authors.initials: R
authors.lastname: Havinga
authors.forename: F
authors.initials: F
authors.lastname: Stellaard
authors.forename: R
authors.initials: R
authors.lastname: Boverhof
authors.forename: F
authors.initials: F
authors.lastname: Kuipers
authors.forename: H M
authors.initials: HM
authors.lastname: Princen
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002635:Chenodeoxycholic Acid / Q000096:biosynthesis; D020355:Cholates / Q000096:biosynthesis; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072469:Cytochrome P450 Family 3; D004764:Enterohepatic Circulation; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D020355:Cholates; D012333:RNA, Messenger; D002635:Chenodeoxycholic Acid; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D000072469:Cytochrome P450 Family 3; C071543:cytochrome P450 CYP3A10 (hamster); D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; D013253:Steroid 12-alpha-Hydroxylase