Accumulation of 7 alpha-hydroxycholesterol in liver tissue of patients with cholesterol gallstones.
Patients with cholesterol gallstones have a reduced pool of bile acids. This study was undertaken to clarify the mechanism by which bile acid biosynthesis does not increase to supranormal levels to cause a reexpansion of the pool. We investigated the first two steps of the bile acid biosynthesis pathway by assaying the activities of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in this pathway, and 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase, and by measuring the concentrations of 7 alpha-hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one in liver specimens from ten patients with cholesterol gallstones and ten gallstone-free controls. In the patients with gallstones, cholesterol 7 alpha-hydroxylase activity, 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase activity, and hepatic 7 alpha-hydroxy-4-cholesten-3-one concentration did not significantly different from levels in controls, but hepatic 7 alpha-hydroxycholesterol concentration was more than twofold that of controls (12.9 +/- 2.6 vs 5.3 +/- 1.2 nmol/g liver, P < 0.01). The concentration of 7 alpha-hydroxycholesterol positively correlated with the ratio of cholesterol 7 alpha-hydroxylase activity to 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase activity (r = 0.93; P < 0.005) in the gallstone-free controls. In contrast, this correlation disappeared in the patients with gallstones. These results suggest a derangement of the normal 7 alpha-hydroxycholesterol metabolism in the patients with gallstones. The reason for the accumulation of 7 alpha-hydroxycholesterol remains unclear; however, it is possible that, in patients with cholesterol gallstone, the accumulated 7 alpha-hydroxycholesterol causes inappropriate suppression of cholesterol 7 alpha-hydroxylase activity by product inhibition.
Honda
A
A
Department of Gastroenterology, University of Tsukuba, Japan.
Yoshida
T
T
Tanaka
N
N
Matsuzaki
Y
Y
He
B
B
Shoda
J
J
Osuga
T
T
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D001706:Biopsy; D002769:Cholelithiasis / Q000378:metabolism*; D002783:Cholestenones / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008875:Middle Aged; D013250:Steroid Hydroxylases / Q000378:metabolism
D002783:Cholestenones; D006888:Hydroxycholesterols; C002656:7 alpha-hydroxy-4-cholesten-3-one; C011724:cholest-5-en-3 beta,7 alpha-diol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D015096:3-Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase