Studies on the role of cytochrome P4501B1 in human chemical carcinogenesis

This dissertation describes the characterization of human cytochrome P4501B1 by its metabolism activities for procarcinogens and its expression in extra-hepatic tissues. Preliminary studies have indicated that cytochrome P4501B1 is capable of bioactivating a wide range of diverse procarcinogens, such as polycyclic aromatic hydrocarbons and heterocyclic amines. In order to directly compare the activity of cytochrome P4501B1 with cytochromes P4501A1 and 1A2, we used recombinantly-expressed proteins to examine the metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol. Cytochrome P4501B1 was fully capable of catalyzing the formation of the proximate and ultimate carcinogens of benzo[a]pyrene, at approximately half the rate of cytochrome P4501A1. To examine the expression of cytochrome P4501B1 in human tissues, a recently developed highly specific polyclonal antibody was used in immunoblotting and immunohistochemistry techniques. Cytochrome P4501B1 expression was characterized in greater detail in human colon and human lung tissues. The widespread expression of cytochrome P4501B1 indicates that this enzyme is capable of the extra-hepatic metabolism and bioactivation of procarcinogens.