The susceptibility of an individual to the deleterious effects of environmental carcinogens is determined by a number of physiological and biochemical factors. One such determinant factor is the capacity of enzymes in the cell of that individual to convert these harmful compounds to forms that are more, or less, harmful to the cell. The proposed studies will concentrate on the identification and characterization of interindividual metabolic differences in the human lung, both with respect to multiple forms of a specific enzyme type (e.g. cytochrome P-450 isozymes or structurally unrelated epoxide hydrolases), and to variants of a single specific enzyme form (microsomal epoxide hydrolase). The proposed studies will seek to identify and quantitate the degree of variation that exists in the human population with regard to these carcinogen-metabolizing enzymes. Two specific areas of research are proposed. In the first, multiple forms of epoxide hydrolases will be examined in human lung. A second project will involve identification of the major forms of cytochrome P-450 present in the human lung. The projects proposed have similar goals in that they both seek to identify and characterize those differences in enzymatic activities which affect the ability of a specific individual or group of cells to respond to the challenge of harmful environmental chemicals. Because these enzymes can potentiate the toxicity of, as well as detoxify, a vast range of foreign compounds, the study of interindividual variability of carcinogen- metabolizing enzymes will provide key insights into the reasons why some individuals are highly susceptible to the carcinogenic effects of environmental chemicals, while others who are similarly exposed are not.
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