ORGAN AND SPECIES DIFFERENCES IN CHEMICAL CARCINOGENS

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The ability of human and rodent tissues to metabolize known or suspected chemical carcinogens is being investigated. The metabolic profiles and genetic toxicities of the chemicals with human tissue activation are then being compared to the results from rodent tissues. Human and rodent liver and kidney cell metabolism of the model carcinogens, benzo (a) pyrene and acetylaminofluorene, have been studied. For human liver, nine individual tissue specimens have been investigated and for acetylaminofluorene eight of the nine human samples were more active metabolizers than the rat hepatocytes. The interindividual variation in the overall human metabolism was about 3-fold, although variation in individual metabolites was as high as 35-fold. The ability of human hepatocytes to conjugate these hydroxylated products with sulfate or glucuronic acid was also greater than in rat hepatocytes and the human interindividual variation to conjugate was about 8-fold. For benzo(a) pyrene, the differences in total metabolism between human hepatocytes and rat hepatocytes were less. Studies with kidney tissues have also indicated that human cells are more active than rat kidney cells in producing acetylaminofluorene metabolites; but kidney cells from both species are less active than hepatocytes. Again, about a 3-fold interindividual variation in human kidney metabolism was observed. Again with benzo(a) pyrene, differences in total metabolism between human and rodent metabolism between human and rat kidney cells were less than for acetylaminofluorene. The findings indicate that the extent of interindividual variations can vary with the chemical being studied. Furthermore, differences between human and rodent metabolism of chemical carcinogens can also vary with the chemical class, and understanding these species differences will be necessary in the extrapolation of rodent carcinogenesis data to humans.