Ethanol interferes with regeneration-associated changes in biotransforming enzymes: a potential mechanism underlying ethanol's carcinogenicity?
The effects of chronic ethanol consumption on enzyme systems involved in carcinogen activation and detoxification were studied in a rat model of liver regeneration. In control rats, steady-state messenger RNAs of cytochrome P450j decreased 12 to 24 hr after partial hepatectomy but were fully recovered by 48 to 72 hr. In contrast, messenger RNA levels of cytochrome P450b and P450d did not vary significantly during that period. Steady-state messenger RNA levels for the placental form of glutathione S-transferase decreased within 30 min after partial hepatectomy but fluctuated until levels returned to normal by 48 hr. Preliminary nuclear run-on analyses suggest that the regulation of cytochrome P450j and the placental form of glutathione S-transferase messenger RNA levels involves posttranscriptional control in these animals. In ethanol-fed rats, as in controls, expression of cytochrome P450j and the placental form of glutathione S-transferase decreased transiently after partial hepatectomy. However, compared with control values, messenger RNA levels for cytochrome P450j were greater in ethanol-fed rats at each time point. Similar results were noted for placental glutathione S-transferase levels from 12 to 48 hr after partial hepatectomy. Ethanol feeding had no apparent effect on steady-state messenger RNA levels of cytochrome P450d, P450b or the multidrug-resistant gene. In both ethanol and control rats, only prehepatectomy levels of cytochrome P450 transcripts correlated with levels of the respective P450 isoenzymes. These data indicate that liver regeneration selectively decreases the steady-state messenger RNA expression of certain isoenzymes of cytochrome P450 and glutathione S-transferase.(ABSTRACT TRUNCATED AT 250 WORDS)
Diehl
A M
AM
Department of Medicine, Veterans Affairs Medical Center, Washington D.C. 20422.
Bisgaard
H C
HC
Kren
B T
BT
Steer
C J
CJ
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011920:Rats, Inbred WF; D014158:Transcription, Genetic
D002273:Carcinogens; D007527:Isoenzymes; D012333:RNA, Messenger; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase