Focal nuclear hepatocyte response to oxidative damage following low dose thioacetamide intoxication.
Rats were treated with low doses of the hepatocarcinogen thioacetamide. Forty-eight hours following this treatment, microscopic foci of hepatic injury were observed, which were surrounded by a peripheral rim of histologically normal hepatocytes. These peripheral hepatocytes generally contained enlarged nuclei, and showed nuclear staining for 4-hydroxynonenal-protein adducts, indicative of nuclear oxidative damage. In these same hepatocytes, we also observed specific focal nuclear induction of mu-class glutathione-S-transferase and alcohol dehydrogenase I, two enzymes which are important in metabolism of 4-hydroxynonenal. Of particular interest was the concurrent nuclear induction of APE/ref-1, a multifunctional DNA repair enzyme which can function as a redox factor, and of the transcription factor Jun, whose DNA binding is facilitated by APE/ref-1. These results document an orchestrated focal nuclear response to oxidative damage produced by thioacetamide administration, and may relate to the permanent effects produced by this treatment.
Clawson
G A
GA
Department of Pathology, Biochemistry & Molecular Biology, The Pennsylvania State University School of Medicine, Milton S. Hershey Medical Centre, Hershey 17033, USA.
Benedict
C M
CM
Kelley
M R
MR
Weisz
J
J
D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D005982:Glutathione Transferase / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008190:Lyases / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000633:toxicity*
D000447:Aldehydes; D016755:Proto-Oncogene Proteins c-jun; D013853:Thioacetamide; D000426:Alcohol Dehydrogenase; D005982:Glutathione Transferase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D008190:Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C027576:4-hydroxy-2-nonenal