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 variationwas found in the ability of 17 human liver S9 samples to mediatethe mutagenicity of 2-acetylaminofluorene (2AAF) in Salmonellatyphimurium strain TA98. In an animal model, variation in metabolicactivation of 2AAF did not appear to relate to the phenotypeof debrisoquine 4-hydroxylase since hepatic S9 from poor andextensive metabolizer phenotypes (female DA and female Wistarrat, respectively) mediated the mutagenicity of this aromaticamide equally well. Approximately onethird of human liver samplesexhibited an ability to detoxify 2AAF in a modified bacterialmutagenicity assay in a manner similar to that shown by guineapig (but not rat or rabbit) S9. However, only in 2/14 humanpreparations was the detoxification inhibited by 8-hydroxyquinolinewhich has previously been recognized as an inhibitor of a detoxifying‘transoxygenation’ in guinea pig liver. The resultssupport a growing body of evidence for inter-individual variationin human carcinogen metabolism which may be important in determiningsusceptibility to chemical carcinogenesis.