DISTRIBUTION OF GLUTATHIONE-S-TRANSFERASE ISOFORMS IN RAT-LIVER AFTERINDUCTION BY BETA-NAPHTHOFLAVONE OR 3-METHYLCHOLANTHRENE

Regional differences in vulnerability to xenobiotic liver damage may r elate to the distribution of the detoxication capacity of the glutathi one S-transferases (GST). HPLC analysis of cell lysates obtained by di gitonin infusion from either the periportal or the perivenous region r evealed that the content of all the GST subunits investigated (1, 2, 3 , 4 and 8) was higher in the perivenous region. The strongest periveno us dominance was observed for subunit 1 (Ya) and the ct class appeared to be more zonated that the mu class. A similar perivenous dominance was observed by analysis of GST activity with either 1-chloro-2,4-dini trobenzene (CDNB), 1,2-dichloronitrobenzene (DCNB) or trans-4-phenyl-3 -buten-2-one (PBO) as substrate. In contrast, with cumene hydroperoxid e (CuOOH) or tert-butyl hydroperoxide (tBOOH) as substarate a reciproc al twofold periportal dominance was observed. Induction by pretreatmen t with beta-naphthoflavone reduced or abolished the perivenous dominan ce of the alpha subunits 1, 2 and 8. In contrast, after pretreatment w ith 3-methylcholanthrene, only the acinar gradient of subunits 2 (Yc) was abolished, while the strong perivenous gradient subunit 1 (Ya) was maintained and that of subunit 8 (Yk) increased. CDNB based assays de monstrated that beta-naphtoflavone treatment reduced (from 2.1 to 1.4) while 3-methyl cholanthrene enhanced (to 2.6) the perivenous/periport al GST activity ratio. Assays based on CuOOH or tBOOH indicated that n either the Se-dependent nor the Se-independent glutathione peroxidase activity nor its acinar distribution was affected by the inducers. The se results demonstrated that although the expression of all investigat ed members of the alpha and mu classes is higher in the perivenous reg ion, there are marked isozyme differences, the acinar gradient being p articularly prominent for subunit 1 (Ya). The distinct difference in t he acinar induction pattern of GST Ya between beta-naphthoflavone and 3-methylcholanthrene resembles that reported for cytochrome P450 (CYP1 A1 and CYP1A2), also members of the aryl hydrocarbon (Ah) receptor gen es, suggesting common regionally acting regulatory elements in the exp ression of these genes in the liver.