This investigation addresses the interrelated problems of A) Uptake and vascular transport of lipophilic chemical carcinogens, and intracellular interactions between lipoproteins and carcinogens; B) Biochemical mechanisms by which polynuclear aromatic hydrocarbon carcinogens inhibit the replicative and repair DNA synthesis in cells. The results observed in this study suggest that ingested benzo(a)pyrene (BaP) enters the gastrointestinal lymphatic drainage sequestered within lymphatic lipoproteins, and that low-density lipoproteins (LDL) play a major role in the vascular transport of BaP. BaP is taken up into cells by adsorptive endocytosis mediated by an interaction between apolipoprotein-specific receptors on the cell membrane and the specific apolipoproteins on LDL. Having entered peripheral cells sequestered within the lipid core of LDL, an electrophilic metabolite of BaP covalently binds to cellular DNA, and may interact with other cellular macro-molecules. Data presented here suggest that LDL is also absolutely required for the activation of DNA polymerase-a, which is the major enzyme of DNA excision repair necessary to correct the DNA damage caused by BaP. This study concludes that an active metabolite of the polynuclear aromatic hydrocarbon carcinogen, benzo(a)pyrene, suppresses DNA polymerase-a activity by inhibiting the binding of 2'-deoxyguanosine 5'-triphosphate to an acceptor site on the DNA polymerase-a complex with the DNA substrate, thereby competitively inhibiting interaction of 2'-deoxyguanosine 5'-triphosphate in the DNA synthetic process.
| Identifer | oai:union.ndltd.org:unt.edu/info:ark/67531/metadc331755 |
| Date | 12 1900 |
| Creators | Joe, Cheol O., 1949- |
| Contributors | Busbee, David L., Donahue, Manus J., Goven, Arthur James, 1950-, McMillin, David, Zimmerman, Earl G. |
| Publisher | North Texas State University |
| Source Sets | University of North Texas |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Format | vi, 101 leaves: ill., Text |
| Rights | Public, Joe, Cheol O., 1949-, Copyright, Copyright is held by the author, unless otherwise noted. All rights reserved. |
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