Selective inhibition of CYP27A1 and of chenodeoxycholic acid synthesis in cholestatic hamster liver.
The aim of this study was to explore the regulation of serum cholic acid (CA)/chenodeoxycholic acid (CDCA) ratio in cholestatic hamster induced by ligation of the common bile duct for 48 h. The serum concentration of total bile acids and CA/CDCA ratio were significantly elevated, and the serum proportion of unconjugated bile acids to total bile acids was reduced in the cholestatic hamster similar to that in patients with obstructive jaundice. The hepatic CA/CDCA ratio increased from 3.6 to 11.0 (P<0.05) along with a 2.9-fold elevation in CA concentration (P<0.05) while the CDCA level remained unchanged. The hepatic mRNA and protein level as well as microsomal activity of the cholesterol 7alpha-hydroxylase, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase and 5beta-cholestane-3alpha,7alpha,12alpha-triol 25-hydroxylase were not significantly affected in cholestatic hamsters. In contrast, the mitochondrial activity and enzyme mass of the sterol 27-hydroxylase were significantly reduced, while its mRNA levels remained normal in bile duct-ligated hamster. In conclusion, bile acid biosynthetic pathway via mitochondrial sterol 27-hydroxylase was preferentially inhibited in bile duct-ligated hamsters. The suppression of CYP27A1 is, at least in part, responsible for the relative decreased production of CDCA and increased CA/CDCA ratio in the liver, bile and serum of cholestatic hamsters.
Matsuzaki
Yasushi
Y
Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, 305-8575 Ibaraki, Japan. ymatsuzaki-gi@umin.ac.jp
Bouscarel
Bernard
B
Ikegami
Tadashi
T
Honda
Akira
A
Doy
Mikio
M
Ceryak
Susan
S
Fukushima
Sugano
S
Yoshida
Shigemasa
S
Shoda
Junichi
J
Tanaka
Naomi
N
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis; D001646:Bile / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000032:analysis / Q000096:biosynthesis*; D053493:Cholestanetriol 26-Monooxygenase; D002779:Cholestasis / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000032:analysis / Q000235:genetics; D006224:Cricetinae; D051544:Cytochrome P-450 CYP3A; D004195:Disease Models, Animal; D015536:Down-Regulation; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D013253:Steroid 12-alpha-Hydroxylase / Q000032:analysis; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics
D012333:RNA, Messenger; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; D013253:Steroid 12-alpha-Hydroxylase; D010089:Oxidoreductases, N-Demethylating