Methylbenz(a)anthracenes (MBAs) have been found in cigarette smoke condensates, stack gas and roofing tar extracts and are potentially environmental hazards to man. Among the twelve isomeric MBAs, 7-MBA is the most active skin carcinogen, 6-, 8-, 12-MBA are less active, and other MBAs are either inactive or slightly active when injected subcutaneously or painted on the skin of rats or mice. The molecular basis for the different carcingenicities of the twelve MBAs is currently unknown. Since MBAs require metabolism to exert their carcinogenicity, the possible differences in their metabolic pathways which may account for their relative carcinogenic potencies will be investigated. The proposed studies are: (1) synthesis of unlabeled and tritium-labeled MBAs; (2) detailed regioselective and stereoselective metabolic studies of each MBA in rat liver microsomes in vitro and in mouse skin in vivo; (3) identification of metabolites formed enzymatically from each MBA by high-performance liquid chromatography, ultraviolet and fluorescence spectrophotometry, mass and nuclear magnetic resonance spectroscopy, and spectropolarimetry; (4) studies on the regioselectivity and stereoselectivity of cytochrome P-450 isozymes and epoxide hydrolase of rat liver microsomal preparations in vitro and in mouse skin in vivo by analyzing the epoxide and dihydrodiol metabolites formed by using molecular oxygen-18 and oxygen-18 water and by chiral stationary phase high-performance liquid chromatography; (5) large-scale preparations of MBA metabolites by enzymic and/or chemical methods; (6) determination of relative mutagenic activities of MBA and metabolites with Salmonella typhimurium tester strain TA100; (7) DNA binding activities of MBAs in mouse skin in vivo; and (8) tumor-initiating activities of the MBAs and their metabolites on mouse skin. These studies will provide detailed understanding of the structure-activity relationships of the twelve MBAs and the molecular basis of their relative carcinogenic potencies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA029133-05
Application #
3168552
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-08-01
Project End
1990-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
U.S. Uniformed Services University of Health Science
Department
Type
Schools of Medicine
DUNS #
City
Bethesda
State
MD
Country
United States
Zip Code
20814
Shou, M; Yang, S K (1996) 3-Hydroxymethylcholanthrene: metabolic formation from 3-methylcholanthrene and stereoselective metabolism by rat liver microsomes. Drug Metab Dispos 24:595-601
Lu, X L; Guengerich, F P; Yang, S K (1991) Stereoselective metabolism of prazepam and halazepam by human liver microsomes. Drug Metab Dispos 19:637-42
Liu, K; Guengerich, F P; Yang, S K (1991) Enantioselective hydrolysis of lorazepam 3-acetate by esterases in human and rat liver microsomes and rat brain S9 fraction. Drug Metab Dispos 19:609-13
Shou, M G; Yang, S K (1990) Metabolism of 2S-hydroxy-3-methylcholanthrene by rat liver microsomes. Carcinogenesis 11:2037-45
Shou, M G; Yang, S K (1990) Enantioselective aliphatic hydroxylations of racemic 1-hydroxy-3-methylcholanthrene by rat liver microsomes. Chirality 2:141-9
Yang, S K; Mushtaq, M; Fu, P P (1990) Absolute configuration of cis-5,6-dihydrodiol enantiomers derived from helical conformers of 1,12-dimethylbenz[a]anthracene. Chirality 2:58-64
Shou, M; Yang, S K (1990) 9,10-Dihydroxy-9,10-dihydro-3-methylcholanthrene-2-one: a principal metabolite of the potent carcinogen 3-methylcholanthrene-2-one by rat liver microsomes. Carcinogenesis 11:689-95
Weems, H B; Yang, S K (1990) Resolution of enantiomeric triols, triol-hydroxyethylthioethers, and methoxy-triols derived from three benzo[a]pyrene diol-epoxides by chiral stationary phase high-performance liquid chromatography. J Chromatogr 535:239-53
Yang, S K; Prasanna, P; Weems, H B et al. (1990) Metabolism of the potent carcinogen 3-methylcholanthrylene by rat liver microsomes. Carcinogenesis 11:1195-201
Shou, M; Yang, S K (1990) 1-Hydroxy- and 2-hydroxy-3-methylcholanthrene: regioselective and stereoselective formations in the metabolism of 3-methylcholanthrene and enantioselective disposition in rat liver microsomes. Carcinogenesis 11:933-40

Showing the most recent 10 out of 24 publications