Title
Differential effects of 17alpha-ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat
Author
Gaubius instituut TNO
Koopen, N.R.
Post, S.M.
Wolters, H.
Havinga, R.
Stellaard, F.
Boverhof, R.
Kuipers, F.
Princen, H.M.G.
Publication year
1999
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 Δ22- 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- 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.
Subject
Δ-22-beta-muricholate
Bile
Cholestasis
Cholesterol-7alpha- 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
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TNO identifier
280457
ISSN
0022-2275
Source
Journal of Lipid Research, 40 (40), 100-108
Document type
article