Comparison of human and rat hepatocyte metabolism and mutagenic activation of 2-acetylaminofluorene.
A method has been developed to assess the metabolism and mutagenic activation of carcinogens using human and rodent hepatocytes in vitro. A slicing technique which was especially useful for nonperfusable biopsy and resected surgical human liver tissue was used to prepare the hepatocytes. Metabolites of the model carcinogen 2-acetylaminofluorene (AAF) produced by human and rat hepatocytes were similar and consisted primarily of 2-aminofluorene with ring hydroxylated products at the 1-, 3-, 5/9-, 7-, and 8-positions produced in addition to N-hydroxy-AAF. Sulphate and glucuronide conjugates of ring-hydroxylated metabolites and 2-aminofluorene were detected. Metabolism and cell-mediated Salmonella mutagenicity illustrated interindividual variation with human hepatocytes. Levels of metabolism and mutagenesis were generally higher with human hepatocytes compared to rat hepatocyte results. The increased levels of metabolism and mutagenesis of AAF by human hepatocytes compared to rat hepatocytes probably indicates a different sensitivity to hepatocarcinogenic effects of AAF on humans as compared to rats. Understanding differences and similarities between human and rodent carcinogen activation capabilities should be useful in the extrapolation of rodent carcinogenesis data to humans.
Rudo
K
K
Cellular and Genetic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Meyers
W C
WC
Dauterman
W
W
Langenbach
R
R
D015073:2-Acetylaminofluorene / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001706:Biopsy; D001711:Biotransformation; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013045:Species Specificity
D009153:Mutagens; D015073:2-Acetylaminofluorene