The susceptibility of an individual to the deleterious effects of environmental toxins and 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 population, 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). Three specific areas of research are proposed. In the first, multiple forms of epoxide hydrolases will be examined in human liver and lung. A second project will involve identification of the major forms of cytochrome P450 present in the human lung. A third related project will investigate the role of xenobioticmetabolizing enzymes in the resistance of individual melanoma tumors to the antineoplastic effects of the chemotherapeutic agent 5(3,3dimethyl1triazeno)imidazole4- carboxamide (DTIC). The three projects proposed have similar goals in that they all seek to identify and characterize those differences in enzymatic activites 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 xenobiotic-metabolizing enzymes will provide key insights into the reasons why some individuals are highly susceptible to the toxic or carcinogenic effects of environmental chemicals, while others who are similarly exposed are not.
| Jevtovic-Todorovic, V; Guenthner, T M (1992) Depletion of a discrete nuclear glutathione pool by oxidative stress, but not by buthionine sulfoximine. Correlation with enhanced alkylating agent cytotoxicity to human melanoma cells in vitro. Biochem Pharmacol 44:1383-93 |
| Jevtovic-Todorovic, V; Guenthner, T M; Jevtoric-Todorovic, V (1991) Sensitization of human melanoma cells to melphalan cytotoxicity by adriamycin and carmustine. J Cancer Res Clin Oncol 117:313-20 |
| Qato, M K; Reinmund, S G; Guenthner, T M (1990) Production of monospecific antiserum to a cytosolic epoxide hydrolase from human liver. Biochem Pharmacol 39:293-300 |
