Carcinogenic polycyclic aromatic hydrocarbons (PAH) are known to undergo enzymatic activation to bay region diol epoxide (BRDE) metabolites which bind covalently to nucleic acids in mammalian cells. While there is strong evidence that alkylation of DNA by these reactive metabolites is critical, there remain many uncertainties concerning the specific details of the molecular mechanisms of PAH carcinogenesis. This proposal is directed towards elucidation of several key mechanistic questions: (i) Is the intercalation of BRDEs into the DNA helix essential or incidental to the mechanism of PAH carcinogenesis? (ii) What is the molecular basis of the remarkable enhancing effect of methyl substitution in nonbenzo ring bay region positions on carcinogenicity (e.g. DMBA and 5-methylchrysene compared to BA and chrysene)Delta (iii) Does the mode of covalent binding to DNA of the BRDEs of the most potent carcinogenic PAH differ significantly with respect to extent of reaction, regio- and stereospecificity of base site attack, the structures of the adducts formed, etc. from that of the BRDEs of biologically less active PAH? Prior investigations of the interaction of the activated BRDE metabolites of PAH have been limited mainly to the BRDE derivatives of benzo[a]pyrene. Since these reactions relatively complex, it is important to distinguish details of the reaction pathway which are critical from those which are irrelevant to bioactivity. Specifically, it is proposed to synthesize the dihydrodiol and BRDE metabolites of a series of 1-alkyl-BaP compounds (R = Me, Et, i-Pr, t-Bu), 5-methylchrysene, 11-methylbenzo[a]pyrene, and 3-methylcholanthrene. The (+)- and (-)enantiomers of the dihydrodiols will be resolved and converted to the corresponding optically pure BRDEs. These compounds will be employed as standards for metabolism studies and their reactions with DNA will be investigated to determine relative extents of reaction, regio- and sterospecifity of attack on the DNA helix, and the structures of the DNA adducts. The findings will be related to the molecular structures and tumorigenicities of these metabolites and the parent PAH.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036097-02
Application #
3173588
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1984-03-01
Project End
1987-02-28
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Flowers-Geary, L; Bleczinki, W; Harvey, R G et al. (1996) Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbon ortho-quinones produced by dihydrodiol dehydrogenase. Chem Biol Interact 99:55-72
Flowers-Geary, L; Harvey, R G; Penning, T M (1995) Identification of benzo[a]pyrene-7,8-dione as an authentic metabolite of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene in isolated rat hepatocytes. Carcinogenesis 16:2707-15
Flowers-Geary, L; Harvey, R G; Penning, T M (1993) Cytotoxicity of polycyclic aromatic hydrocarbon o-quinones in rat and human hepatoma cells. Chem Res Toxicol 6:252-60
Jarabak, J; Harvey, R G (1993) Studies on three reductases which have polycyclic aromatic hydrocarbon quinones as substrates. Arch Biochem Biophys 303:394-401
Shou, M; Harvey, R G; Penning, T M (1993) Reactivity of benzo[a]pyrene-7,8-dione with DNA. Evidence for the formation of deoxyguanosine adducts. Carcinogenesis 14:475-82
Nair, R V; Nettikumara, A N; Cortez, C et al. (1992) Comparative metabolism of dibenz[a,j]anthracene and 7-methyldibenz[a,j]anthracene in primary cultures of mouse keratinocytes. Chem Res Toxicol 5:532-40
Flowers-Geary, L; Harvey, R G; Penning, T M (1992) Examination of diols and diol epoxides of polycyclic aromatic hydrocarbons as substrates for rat liver dihydrodiol dehydrogenase. Chem Res Toxicol 5:576-83
Shou, M; Harvey, R G; Penning, T M (1992) Contribution of dihydrodiol dehydrogenase to the metabolism of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene in fortified rat liver subcellular fractions. Carcinogenesis 13:1575-82
Nair, R V; Gill, R D; Nettikumara, A N et al. (1991) Characterization of covalently modified deoxyribonucleosides formed from dibenz[a,j]anthracene in primary cultures of mouse keratinocytes. Chem Res Toxicol 4:115-22
Bigger, C A; Flickinger, D J; Strandberg, J et al. (1990) Mutational specificity of the anti 1,2-dihydrodiol 3,4-epoxide of 5-methylchrysene. Carcinogenesis 11:2263-5

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