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

Citation
Nr. Koopen et al., Differential effects of 17 alpha-ethinylestradiol on the neutral and acidic pathways of bile salt synthesis in the rat, J LIPID RES, 40(1), 1999, pp. 100-108
Citations number
46
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF LIPID RESEARCH
ISSN journal
0022-2275 → ACNP
Volume
40
Issue
1
Year of publication
1999
Pages
100 - 108
Database
ISI
SICI code
0022-2275(199901)40:1<100:DEO1AO>2.0.ZU;2-0
Abstract
Effects of 17 alpha-ethinylestradiol (EE) on the neutral and acidic biosynt hetic pathways of bile salt (BS) synthesis were evaluated in rats with an i ntact enterohepatic circulation and in rats with long-term bile diversion t o induce BS synthesis, For this purpose, bile salt pool composition, synthe sis of individual BS in vivo, hepatic activities, and expression levels of cholesterol 7 alpha-hydroxylase (CYP7A), and sterol 27-hydroxylase (CYP27), as well as of other enzymes involved in BS synthesis, were analyzed in rat s treated with EE (5 mg/kg, 3 days) or its vehicle, BS pool size was decrea sed by 27% but total BS synthesis was not affected by EE in intact rats. Sy nthesis of cholate was reduced by 68% in EE-treated rats, while that of che nodeoxycholate was increased by 60%, The recently identified Delta(22)-isom er of beta-muricholate contributed for 5.4% and 18.3% (P < 0.01) to the poo l in control and EE-treated rats, respectively, but could not be detected i n 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 int act and bile-diverted rats, whereas the activity of the CYP27 was not affec ted, 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 12 alpha-hydroxylase and lithocholate 6 beta-hydroxy lase were increased by bile diversion and suppressed by EE. This study show s that 17 alpha-ethinylestradiol (EE)-induced intrahepatic cholestasis in r ats is associated with selective inhibition of the neutral pathway of bile salt (BS) synthesis. Simultaneous impairment of other enzymes in the BS bio synthetic pathways may contribute to overall effects of EE on BS synthesis.