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.
Smith
A J
AJ
Department of Biochemistry, University of Birmingham, UK.
Chipman
J K
JK
D015073:2-Acetylaminofluorene / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D005260:Female; D014644:Genetic Variation; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests / Q000379:methods; D009154:Mutation; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D013045:Species Specificity
D015073:2-Acetylaminofluorene