Inter-individual variation in the mutagenic activation of 2-acetylaminofluorene by human liver in relation to animal metabolic models.

A relatively large, reproducible inter-individual variation was found in the ability of 17 human liver S9 samples to mediate the mutagenicity of 2-acetylaminofluorene (2AAF) in Salmonella typhimurium strain TA98. In an animal model, variation in metabolic activation of 2AAF did not appear to relate to the phenotype of debrisoquine 4-hydroxylase since hepatic S9 from poor and extensive metabolizer phenotypes (female DA and female Wistar rat, respectively) mediated the mutagenicity of this aromatic amide equally well. Approximately one-third of human liver samples exhibited an ability to detoxify 2AAF in a modified bacterial mutagenicity assay in a manner similar to that shown by guinea pig (but not rat or rabbit) S9. However, only in 2/14 human preparations was the detoxification inhibited by 8-hydroxyquinoline which has previously been recognized as an inhibitor of a detoxifying 'transoxygenation' in guinea pig liver. The results support a growing body of evidence for inter-individual variation in human carcinogen metabolism which may be important in determining susceptibility to chemical carcinogenesis.