Research Interests
Ward G. Kirlin, Ph.D.
Individual susceptibility to chemical carcinogens and environmental toxins is dependent on the metabolic balance between bioactivation and detoxification enzymes. Therefore, the relative activities of biotransformation enzymes, (e.g. cytochrome P450 1A, glutathione S-transferases and NAD(P)H:quinone oxidoreductase) are important determinants of the metabolic fate of carcinogens, such as benzo[a]pyrene, that can be activated to electrophiles to form DNA adducts or detoxified for elimination. A major detoxification route involves conjugation with the protective cytoplasmic thiol, glutathione. Our primary research focus involves the relationship between oxidative stress and transcriptional regulation of carcinogen metabolizing enzymes. Many dietary phytochemicals have been identified that appear to alter steps in the enzymatic biotransformation of carcinogens that involve regulatory mechanisms influenced by the intracellular oxidation-reduction potential. Conditions, such as oxidative stress, that shift the concentrations of reduced and oxidized glutathione:glutathione disulfide and/or cysteine:cystine alter enzyme expression through interactions between specific DNA promoter response elements and specific transcription proteins. Translocation of proteins from the cytoplasm to the nucleus and the affinity of these proteins for binding to transcription promoter sequences are also influenced by the cellular redox state that may be altered in response to electrophiles, antioxidants and oxidative stress. Our studies utilize a variety of human cell lines that express differing levels of carcinogen metabolizing enzymes and that have been transfected with reporter constructs to indicate alterations in transcriptional regulation. It is critical to our understanding of the role of dietary chemicals in cancer prevention to also understand their affect on oxidative stress and metabolic activation of carcinogens. Individual variation in the relative expression of carcinogen metabolizing enzymes may be a key factor in differing individual susceptibilities to carcinogens.
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