Polycyclic aromatic hydrocarbons (PAH's) are probably the most widely distributed pollutants in the world. Their mutagenicity and carcinogenicity have been extensively studied, but other modes of cytotoxic activity have been neglected. We recently described the very high light-dependent toxicity of many PAH's in important organisms, such as tadpoles, fish, Daphnias, and insects. Even PAH's which are not carcinogenic (and were considered to be harmless) are very phototoxic. The goal of this research is to understand at the cellular and molecular levels the mechanism(s) of light-dependent toxicity of PAH's. This proposal combines the power of microbial genetics with chemical approaches for the determination of the fundamental mechanisms of photoinduced reactions in living organisms. Because of the biological complexity of the organisms mentioned above, the biochemical work will be performed on the microorganism Escherichia coli, which is probably the most completely characterized biological system known. Two targets for possible photosensitized damage will be particularly scrutinized: DNA and membranes. The reaction sites will be determined by genetic and microbiological techniques, utilizing an extensive series of mutants. The detailed molecular changes will be investigated chemically, using radioactive sensitizers, chemical degradation techniques, chromatographic purification, and spectroscopic analyses. A very important part of the work deals with photochemical reactions involving not only the sensitizer and target molecules, but also oxygen, which probably mediates the majority of the phototoxic events, through the formation of singlet oxygen, superoxide ion, hydrogen peroxide, and hydroxyl radicals. PAH's are major components of coal tar and of many petroleum products, and occupational exposure to these compounds affects many workers and the public at large. An understanding of the phototoxic mechanism(s) of PAH's will allow for the development of rational approaches to the threat posed by light-mediated PAH toxicity to biological systems, and for the design of more selective and more efficient sensitizers to be used in biology, chemistry, and medicine.
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