ROLE OF CYTOCHROME P-450 IN CHEMICAL TOXICITY AND CARCINOGENESIS

Abstract

Most chemical carcinogens and toxicants formed in our environment require metabolic activation or detoxification to exert their harmful effects or be rendered harmless, respectively, in their target cells and tissues. The major activation pathway is oxidative metabolism, usually catalyzed by cytochrome P-450-dependent monooxygenase systems. Multiple forms of cytochrome P-450 have been isolated and characterized from certain species of experimental animals. In this review we attempt to present a discussion of 1) specificity of catalytic activity in cytochrome P-450 enzymes in chemical carcinogenesis, 2) distribution of cytochrome P-450 enzymes in different species of experimental animals, 3) specificity of cytochrome-P-450 enzymes in extrahepatic tissues, and 4) genetic regulation in the susoeptibility to cancer in experimental animals and human. One of the important problems is to evaluate the role of extrahepatic cytochrome P-450 in chemical carcinogenesis and toxicity. We know some forms of cytochrome P-450 are highly localized in particular regions or cells, as for example, in non-ciliated bronchiolar (Clara) cells of the lung. Whether or not cytochrome P-450 enzymes and other drug metabolizing enzymes play significant roles in the expression of chemical toxicity in target tissues, may depend on the stability of biologically reactive intermediates mediated in vivo by the liver, the major organ for these enzymes. It is of interest that there is an apparent tissue difference in the expression of the cytochrome P-450IAl gene and in the inducibility of benzo [a] pyrene hydroxylation by 3-methyl-cholanthrene between lung and liver in Syrian golden hamsters. Whenever we attempt to postulate a process explaining the primary prophylaxis leading to chemical carcinogenesis in human, we have to deal with the question of which similarities of cytochrome P-450 and the related drug-metabolizing enzymes encountered in the animal model situations may extend to those of interest in the human populations at potential risk.