Enhanced levels of DNA adducts in the liver of woodchucks infected with hepatitis virus.
Liver DNA specimens from woodchucks kept in captivity, 10 naturally infected with hepatitis virus (WHV) and five WHV-free, were examined for the presence of carcinogen-DNA adducts by 32P-postlabeling. The number of adducts was significantly higher in WHV carriers than in uninfected animals, and the total amounts of adducts per 10(9) nucleotides were also considerably enhanced by WHV infection, when using both butanol extraction (22.2 +/- 7.1 vs. 12.6 +/- 2.8, means +/- S.D.) and nuclease P1 enrichment (8.5 +/- 5.9 vs. 2.8 +/- 1.7). Two individual adducts were also significantly higher in WHV carriers. No significant variation occurred as related to age, sex or time length of captivity. These findings are consistent with our previous studies supporting an enhanced metabolism of chemical hepatocarcinogens in both human and woodchuck hepadnavirus infections. Several significant and remarkable correlations were pointed out by relating DNA adduct data to more than 30 virological, histopathological and metabolic parameters which had been previously evaluated in the same animals. For instance, numbers and/or levels of adducts were positively related to the amounts of virus present in hepatocytes, to cell damage (gamma-glutamyltranspeptidase activity), to the severity of the liver histopathological picture, and to monooxygenase activities, while they were inversely related to cellular glutathione concentrations and to detoxification of the direct-acting mutagen 4-nitroquinoline 1-oxide. The major adduct significantly correlated with the metabolic activation of the aromatic amine 2-aminofluorene and of the heterocyclic amines 3-amino-1-methyl-5H-pyrido(4,3)indole (Trp-P-2) and 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ), whereas another adduct significantly correlated with the metabolic activation of the mycotoxin aflatoxin B1. Thus, the enhanced metabolism of chemical hepatocarcinogens and the increased formation of carcinogen-DNA adducts in the liver of WHV carriers appear to represent one of the mechanisms contributing to the association between chronic hepadnavirus infection and development of primary hepatocellular carcinoma.
Izzotti
A
A
Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
Scatolini
L
L
Lewtas
J
J
Walsh
D
D
De Flora
S
S
D015112:4-Nitroquinoline-1-oxide / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006509:Hepatitis B / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D017919:Hepatitis B Virus, Woodchuck / Q000302:isolation & purification; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D008392:Marmota
D002273:Carcinogens; D018736:DNA Adducts; D015112:4-Nitroquinoline-1-oxide; D005978:Glutathione