Differential lobular induction in rat liver of glutathione S-transferase A1/A2 by phenobarbital

Phenobarbital and other xenobiotics induce drug-metabolizing enzymes, inclu ding glutathione S-transferase A1/A2 (rGSTA1/A2). We examined the mechanism of induction of rGSTA1/A2 in rat livers after phenobarbital treatment. The induction of rGSTA1/A2 was not uniform across the hepatic lobule; steady-s tate transcript levels were threefold higher in perivenous hepatocytes rela tive to periportal hepatocytes when examined by in situ hybridization 12 h after a single dose of phenobarbital. Administration of a second dose of ph enobarbital 12 or 24 h after the first dose did not equalize the induction of rGSTA1/A2 across the lobule. The transcriptional activity of the rGSTA1/ A2 gene was increased 3.5- to 5.5-fold in whole liver by phenobarbital, but activities were the same in enriched periportal and perivenous subpopulati ons of hepatocytes from phenobarbital-treated animals. The half-life of rGS TA1/A2 mRNA in control animals was 3.6 h, whereas it was 10.2 h in phenobar bital-treated animals. We conclude that phenobarbital induces rGSTA1/A2 exp ression by increasing transcriptional activity across the lobule but induct ion of rGSTA1/A2 is greater in perivenous hepatocytes due to localized stab ilization of mRNA transcripts.