Polycyclic aromatic hydrocarbons undergo activation by the AHH mediated biotransformation, and deactivation by conjugating pathways (glucuronidation, sulfation and glutathione conjugation). Since the net carcinogenic effect of a hydrocarbon carcinogen will be affected by the levels of both activating and deactivating processes, it is important to test what role the deactivating pathways play in protection from carcinogenicity by polycyclic hydrocarbons. It is proposed to gain an insight into the role of these factors by studying the fate of benzo(a)pyrene in hepatocytes of different strains of mice, and relate these to hepatocarcinogenesis in selected strains. It is particularly proposed to elucidate the role of glucuronidation in this process, and to obtain basic information regarding the occurrence, properties and substrate specificity of various forms of glucuronyltransferases in liver tissue, and the factors controlling these activities -- environmental (such as inducibility with polycyclic hydrocarbons), and genetic (such as variations in responsiveness to inducing agents). A long range goal is to determine whether suitable model drug substrates can be found, for the various forms of glucuronyltransferases involved in carcinogen metabolism, which would mimic the behavior of the corresponding carcinogenic polycyclic hydrocarbon and thus could be used as probes for the potential metabolism of the carcinogen by those enzymes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024127-06
Application #
3166330
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1978-09-30
Project End
1987-09-29
Budget Start
1985-09-30
Budget End
1986-09-29
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Byczkowski, J Z; Gessner, T (1989) Effects of inhibition of NADPH: cytochrome P-450 reductase on benzo(a)pyrene metabolism in mouse liver microsomes. Int J Biochem 21:525-9
Byczkowski, J Z; Gessner, T (1988) Inhibition of the redox cycling of vitamin K3 (menadione) in mouse liver microsomes. Int J Biochem 20:1073-9
Byczkowski, J Z; Gessner, T (1988) Biological role of superoxide ion-radical. Int J Biochem 20:569-80
Byczkowski, J Z; Gessner, T (1987) Interaction between vitamin K3 and benzo(a)pyrene metabolism in uninduced microsomes. Int J Biochem 19:1173-9
Byczkowski, J Z; Gessner, T (1987) Effects of superoxide generated in vitro on glucuronidation of benzo[a]pyrene metabolites by mouse liver microsomes. Int J Biochem 19:531-7
Byczkowski, J Z; Gessner, T (1987) Asbestos-catalyzed oxidation of benzo(a)pyrene by superoxide-peroxidized microsomes. Bull Environ Contam Toxicol 39:312-7
Byczkowski, J Z; Gessner, T (1987) Action of xanthine-xanthine oxidase system on microsomal benzo(a)pyrene metabolism in vitro. Gen Pharmacol 18:385-95