The long-term objective of the proposed research is to elucidate the molecular basis for the unique ability of dogs to metabolize and eliminate certain highly chlorinated polychlorinated biphenyls (PCBs). PCBs are a class of compounds characterized by a biphenyl nucleus with varying degrees of chlorination on one or both phenyl rings. PCBs have been widely used in industry due to their resistance to thermal, chemical, and biological degradation. Although their production was terminated in the 1970s, PCBs are still in wide use in electrical capacitors and transformers. The high stability of PCBs be led to their persistence in the environment, and because of the serious toxicity associated with many PCBs, they pose a significant human health hazard. One of the key factors that determines the persistence of PCBs in the environment as well as in animal and human tissues is their metabolism. In general, highly chlorinated PCBs, especially those lacking two adjacent unsubstituted sites on one of the phenyl rings, are metabolized slowly by micro-organisms and mammals. One such compound which is highly persistent in the environment and in human tissues and breast milk is 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB). 245-HCB and the related polybrominated compound 2,2',4,4',5,5'-hexabromobiphenyl are both tumor promoters in rats. Of all species tested to date, only the dog appear to be able to efficiently metabolize and eliminate 245-HCB. Recent results from this laboratory have shown that this unique metabolic capability of the dog is due to the presence of a form of cytochrome P-450 called PBD-2 which has a higher hepatic concentration and intrinsic activity towards 245-HCB than the corresponding cytochromes P-450 in other species the proposed research will focus on determining the molecular basis for the unique properties of PBD-2. The individual specific aims are: to determine the nucleotide sequence of cDNA coding for PBD-2, to determine whether the PBD-2 gene is unique or a member of a multigene family, to determine the structure of and the presence of potential regulator elements in the gene(s) coding. for PBD-2, and to determine which domain of the protein is responsible for its unusual ability to metabolize 245-HCB. These studies should provide an explanation for the inability of humans to metabolize certain environmentally important PCBs and may also provide the basis for creating genetically altered bacteria or plants, specifically tailored to detoxify PCBs in the environment.
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