Polycyclic aromatic hydrocarbon carcinogen-DNA interactions. Progress report, September 1, 1979-October 31, 1981
Polycyclic aromatic hydrocarbon (PAH) constitute a well-known class of environmental carcinogens and mutagens, and occur in coal, coal tars and in combustion products of coal-fired plants. In living cells these PAH molecules are metabolized to a variety of oxygenated derivatives. Some of these metabolites, the epoxides and diol epoxides, are chemically very reactive and form chemical adducts with nucleic acids. It is widely believed that the formation of these carcinogen-DNA adducts is the critical step which transforms a normal cell into a pre-cancerous state. In this work, the reaction mechanisms of benzo(a)pyrene diol epoxide (BPDE) with DNA and the structure of the covalent adducts formed have been studied in detail under controlled laboratory conditions in aqueous solutions. When two solutions, one containing BPDE and the other DNA, are mixed rapidly (approx. 5 ms) in a stopped-flow apparatus, a non-covalent BPDE-DNA intercalation complex is formed. The preferred reaction pathway of the diol epoxide at this intercalation site is the nucleophilic addition of water to form the corresponding tetraol, while only 5 to 10% of the BPDE molecules present bind covalently to tthe nucleic acid bases. The DNA-catalyzed hydrolysis of the diol epoxide appears to prevent more extensive covalent adduct formation. The conformation of the covalent BPDE-DNA adduct is quite different from the non-covalent BPDE intercalation complex. In the covalent adduct the pyrenyl moeity appears to be located at an accessible exterior DNA binding site. Analagous experiments with a benzo(a)pyrene epoxide (similar in structure to BPDE but lacking the two OH groups) show that there are at least two different types of binding sites one of which appears to be an exterior site, while the other resembles an intercalation binding site.
- Research Organization:
- New York Univ., NY (USA). Dept. of Chemistry
- DOE Contract Number:
- AS02-78EV04959
- OSTI ID:
- 6081122
- Report Number(s):
- DOE/EV/04959-3; ON: DE82002953
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
01 COAL, LIGNITE, AND PEAT
BENZOPYRENE
BIOCHEMICAL REACTION KINETICS
DNA
ADDUCTS
AQUEOUS SOLUTIONS
CHEMICAL BONDS
MOLECULAR STRUCTURE
AROMATICS
CONDENSED AROMATICS
DISPERSIONS
HYDROCARBONS
KINETICS
MIXTURES
NUCLEIC ACIDS
ORGANIC COMPOUNDS
REACTION KINETICS
SOLUTIONS
550200* - Biochemistry
016000 - Coal
Lignite
& Peat- Health & Safety