Differential lobular induction in rat liver of glutathione S-transferase A1/A2 by phenobarbital.
Phenobarbital and other xenobiotics induce drug-metabolizing enzymes, including 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-state transcript levels were threefold higher in perivenous hepatocytes relative to periportal hepatocytes when examined by in situ hybridization 12 h after a single dose of phenobarbital. Administration of a second dose of phenobarbital 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 subpopulations of hepatocytes from phenobarbital-treated animals. The half-life of rGSTA1/A2 mRNA in control animals was 3.6 h, whereas it was 10.2 h in phenobarbital-treated animals. We conclude that phenobarbital induces rGSTA1/A2 expression by increasing transcriptional activity across the lobule but induction of rGSTA1/A2 is greater in perivenous hepatocytes due to localized stabilization of mRNA transcripts.
Selim
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N
Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Branum
G D
GD
Liu
X
X
Whalen
R
R
Boyer
T D
TD
D000818:Animals; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006207:Half-Life; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014158:Transcription, Genetic
D007527:Isoenzymes; D012333:RNA, Messenger; D005982:Glutathione Transferase; D010634:Phenobarbital