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Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus
1International Agency for Research on Cancer 69372 Lyon, France
2Fox Chase Cancer Center, Institute for Cancer Research Philadelphia, PA 19111, USA
Institute of Hygiene and Preventive Medicine, University of Genoa 16132 Genoa, Italy
The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmotamonax). Of these, 23 were naturally infected with the wood-chuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcelhilar fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as 
-glutamyl transpeptidase, cytochrome P-450 and mirosomal monooxygenases (aryl hydrocarbon hydroxylase, ethodycoumarin and ethoxyresorufin deethylases, amino-pyrine and dimethylnitrosamine demethylases, and testosterone 7
-and 16ß- and 6ß-hydroxylases), uridine 5'-diphos-phoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MelQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium di-chromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of pro-carcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals, without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the turmorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepato-carcinogens in the etiopathogenesis of PHC.
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