PHASE-I AND PHASE-II METABOLISM OF LITHOCHOLIC ACID IN HEPATIC ACINARZONE-3 NECROSIS - EVALUATION IN RATS BY COMBINED RADIOCHROMATOGRAPHY AND GAS-LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY

In the present study, lithocholic acid (LCA) metabolism was assessed b y radiochromatography and gas-liquid chromatography-mass spectrometry, and its relationship to choleslasis was investigated. In addition, th e role of the perivenous zone in LCA-induced cholestasis and LCA biotr ansformation was examined by using bromobenzene (BZ), a chemical that causes selective necrosis of hepatocytes in this zone. LCA injection i nduced cholestasis of comparable amplitude in both control and BZ-trea ted rats. The biliary recovery of bile salts (BS) was 65-70% 2 hr afte r LCA injection. Excretion of LCA and its cholestatic metabolite, LCA glucuronide, was similar in both groups, although LCA excretion was de layed in BZ-treated animals. The appearance of LCA and LCA glucuronide in bile occurred early, and their proportion decreased with time. Con centrations of choleretic hydroxylated metabolites were low immediatel y after LCA injection but increased with time. 3 alpha,6 beta-Dihydrox y-5 beta-cholanoic and 3 alpha,6 beta,7 beta-trihydroxy-5 beta-cholano ic acids were the major species arising from LCA, indicating the impor tance of 6 beta hydroxylation in LCA detoxification in rats. Other met abolites were found, but their contribution was either minor or neglig ible. Overall amounts of hydroxylated metabolites were comparable in b oth groups, but trihydroxylated metabolites predominated over their di hydroxylated counterparts in control rats, whereas the production of d ihydroxylated forms was more pronounced in BZ-treated animals. These r esults suggest that the destruction of perivenous hepatocytes does not exacerbate LCA-induced cholestasis, and that there may be an acinar z onation of LCA biotransformation to trihydroxylated metabolites in the rat liver.