Phase I and phase II metabolism of lithocholic acid in hepatic acinar zone 3 necrosis. Evaluation in rats by combined radiochromatography and gas-liquid chromatography-mass spectrometry.
In the present study, lithocholic acid (LCA) metabolism was assessed by radiochromatography and gas-liquid chromatography-mass spectrometry, and its relationship to cholestasis was investigated. In addition, the role of the perivenous zone in LCA-induced cholestasis and LCA biotransformation was examined by using bromobenzene (BZ), a chemical that causes selective necrosis of hepatocytes in this zone. LCA injection induced cholestasis of comparable amplitude in both control and BZ-treated rats. The biliary recovery of bile salts (BS) was 65-70% 2 hr after LCA injection. Excretion of LCA and its cholestatic metabolite, LCA glucuronide, was similar in both groups, although LCA excretion was delayed in BZ-treated animals. The appearance of LCA and LCA glucuronide in bile occurred early, and their proportion decreased with time. Concentrations of choleretic hydroxylated metabolites were low immediately after LCA injection but increased with time. 3 alpha,6 beta-Dihydroxy-5 beta-cholanoic and 3 alpha,6 beta,7 beta-trihydroxy-5 beta-cholanoic acids were the major species arising from LCA, indicating the importance of 6 beta hydroxylation in LCA detoxification in rats. Other metabolites were found, but their contribution was either minor or negligible. Overall amounts of hydroxylated metabolites were comparable in both groups, but trihydroxylated metabolites predominated over their dihydroxylated counterparts in control rats, whereas the production of dihydroxylated forms was more pronounced in BZ-treated animals. These results suggest that the destruction of perivenous hepatocytes does not exacerbate LCA-induced cholestasis, and that there may be an acinar zonation of LCA biotransformation to trihydroxylated metabolites in the rat liver.
Dionne
S
S
Department of Pharmacology, University of Montreal, Québec, Canada.
Tuchweber
B
B
Plaa
G L
GL
Yousef
I M
IM
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001647:Bile Acids and Salts / Q000032:analysis; D001969:Bromobenzenes; D002250:Carbon Radioisotopes; D002779:Cholestasis / Q000209:etiology*; D002855:Chromatography, Thin Layer; D008401:Gas Chromatography-Mass Spectrometry; D005965:Glucuronates / Q000378:metabolism; D008095:Lithocholic Acid / Q000008:administration & dosage / Q000378:metabolism*; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley
D001647:Bile Acids and Salts; D001969:Bromobenzenes; D002250:Carbon Radioisotopes; D005965:Glucuronates; D008095:Lithocholic Acid; C032036:bromobenzene