Species differences of glucuronidation and sulfation in relation to hepatocarcinogenesis.

The role of glucuronidation and sulfation in the control of proximal and ultimate carcinogens is briefly reviewed. In accordance with the adopted practice of tumor risk assessment, data from two rodent species (rat, mouse) and man have been compared. Sulfate esters have been established as ultimate carcinogens in 2-acetylaminofluorene, safrole and estragole induced hepatocarcinogenesis. In interspecies comparisons the tumor incidence paralleled sulfotransferase activity (Miller and Miller 1981). Glucuronides are often stable transport forms of carcinogens and in this way determine their organ specificity, for example in 2-naphthylamine-induced bladder carcinogenesis and in colon carcinogenesis produced by 2',3-dimethyl-4-aminobiphenyl. In contrast to sulfotransferase activity certain UDP-glucuronyltransferase activities are differentially inducible by xenobiotics. A 3-methylcholanthrene-inducible phenol-glucuronyltransferase (GT1), present in rat, mouse and man, appears to be part of an adaptive program to detoxify aromatic hydrocarbons. After initiation of hepatocarcinogenesis permanent alterations of these enzymes occur; GT1 is markedly increased whereas sulfotransferase is decreased. Together with changes of other drug metabolizing enzymes these alterations often lead to toxin-resistance of initiated hepatocytes. This phenomenon may facilitate selective growth of initiated hepatocytes and may enhance the probability of multiple hits in their genome.