Polycyclic aromatic hydrocarbons (PAHs), including benzo(a)pyrene (BP), form a major class of environmental pollutants suggested to be causative factors in a variety of disease susceptibilities, including cancer. Virtually all PAH mixtures contain BP; a model compound that causes the formation of BP-DNA-adducts. Levels of BP-DNA adducts in cigarette smokers are decreased by vitamin E (a-tocopherol) administration. Although a-tocopherol's antioxidant activity has been the proposed mechanism for its protective effects, our recent provocative findings indicate that a-tocopherol also has a regulatory function in liver. Thus, a-tocopherol's action in eliminating BP-induced DNA damage likely involves regulation of hepatic detoxification and biliary excretion. There is, therefore, a need to evaluate a-tocopherol-dependent modulation of hepatic xenobiotic metabolism and disposition as mechanisms for the detoxification and elimination of PAHs. Our long-range goal is to determine the efficacy of prophylactic high dose vitamin E supplementation for prevention of DNA-adduct formation during occupational exposure to PAHs. Our objective in this R21 application is to identify the key mechanism(s) by which a-tocopherol supplementation alters the response of hepatic, lung and kidney tissues to PAHs utilizing BP as a model compound. Our central hypothesis is that pharmacologic a-tocopherol supplementation, in addition to providing increased antioxidant protection, increases xenobiotic metabolism and excretion pathways, thereby protecting the liver and other organs from PAH-induced DNA adduct formation by increasing detoxification and/or elimination of PAHs and their metabolites from the body. We propose to:
Aim 1. Determine modulation of BP metabolism and excretion by a-tocopherol in rats. Our working hypothesis is that elevated levels of a-tocopherol will significantly increase: (1) metabolism of BP to non-DNA reactive metabolites and (2) increase BP and/or BP metabolite excretion.
Aim 2. Identify the protective effects of a-tocopherol supplementation against BP-induced DNA damage. Our working hypothesis is that elevated levels of a-tocopherol will decrease BP-induced DNA damage in liver, lung and kidney by two synergistic mechanisms: (1) increased antioxidant protection against oxidative stress- induced damage and (2) decreased formation of covalent BP-DNA adducts. This proposal is innovative because it challenges the current paradigm that -tocopherol acts almost exclusively as an antioxidant, while supporting the paradigm that nutrition and dietary regiments can modulate toxicological insults and resultant pathologies. The public health relevance of these studies is that evidence that pathways other than antioxidant activity are functionally operative in a-tocopherol-mediated protection against environmental pollutants such as PAHs would be of considerable value in the ultimate development of protective strategies for acute occupational exposures to these and other environmental pollutants. Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure.
Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure. ? ? ?
