Polycyclic aromatic hydrocarbons undergo activation by the AHH mediated biotransformation, and deactivation by conjugating pathways (glucuronidation, sulfation and glutathione conjugation). Since the net carcinogenic effect of a hydrocarbon carcinogen will be affected by the levels of both activating and deactivating processes, it is important to test what role the deactivating pathways play in protection from carcinogenicity by polycyclic hydrocarbons. It is proposed to gain an insight into the role of these factors by studying the fate of benzo(a)pyrene in hepatocytes of different strains of mice, and relate these to hepatocarcinogenesis in selected strains. It is particularly proposed to elucidate the role of glucuronidation in this process, and to obtain basic information regarding the occurrence, properties and substrate specificity of various forms of glucuronyltransferases in liver tissue, and the factors controlling these activities -- environmental (such as inducibility with polycyclic hydrocarbons), and genetic (such as variations in responsiveness to inducing agents). A long range goal is to determine whether suitable model drug substrates can be found, for the various forms of glucuronyltransferases involved in carcinogen metabolism, which would mimic the behavior of the corresponding carcinogenic polycyclic hydrocarbon and thus could be used as probes for the potential metabolism of the carcinogen by those enzymes.
