ROLE OF HUMAN CYTOCHROME-P-450S IN RISK ASSESSMENT AND SUSCEPTIBILITY TO ENVIRONMENTALLY BASED DISEASE

Cytochromes P-450 (P-450s) are a large group of heme-containing proteins that carry out oxidation of numerous chemicals. In mammals, a limited number of P-450s are involved in metabolic pathways of steroid synthesis, while most of these enzymes are involved in metabolism of foreign compounds. The principal beneficial function of P-450s is to convert chemicals into derivatives that can be easily eliminated from the body. This generally occurs through P-450-mediated oxidations of hydrophobic substances followed by conjugation reactions. For many foreign compounds, P-450 metabolism results in production of ''activated'' metabolites that can cause cell death and gene mutations. During the past several years, it has become widely recognized that marked species differences occur among the foreign compound-metabolizing P-450s. In addition to this interspecies variability in metabolism, marked intraspecies variability, frequently referred to as drug oxidation polymorphisms, occurs in virtually all mammals examined to date. Based on these observations, it is necessary to develop new human P-450-based systems that can be used to study foreign compound metabolism in order to predict human risk. This is being accomplished by use of cDNA-directed expression in B lymphoblastoid cells. These cells can be used to predict how humans will metabolize a chemical and whether it will be metabolically activated to a toxic or mutagenic metabolite. To study human P-450 polymorphisms, polymerase chain reaction (PCR) assays have been developed for diagnosis of known mutant P-450 genes. Molecular probes are also being used to screen populations for levels of expression of carcinogen-activating P-450s in an effort to determine whether expression of certain P-450 forms is associated with increased risk for development of environmentally based disease.