Reactive oxygen species have been shown to be important in a variety of toxic phenomena and may be the mediators of genotoxicity for a variety of carcinogens. The objective of the proposed research is to investigate the hypothesis that certain peroxisome-proliferating chemicals exert their liver carcinogenic effects by increasing intracellular levels of H2O2 giving rise to reactive oxygen species that damage DNA. The chemicals to be studied have been selected on the basis of their diverse chemical structure and the species specificity of their peroxisome-proliferating and hepatocarcinogenic effects. These chemicals include important environmental agents such as the industrial solvent, trichloroethylene, the phthalate plasticizers, and three hypolipidemic agents, two of which are used as human medications. The hepatocarcinogenic effects of these chemicals often occurs in only one rodent species in which induction of peroxisomes is seen. The described hypothetical mechanism will be tested by two experiments. First, the production and metabolism of H2O2 in suspensions of freshly isolated intact hepatocytes fromsusceptible and resistant species exposed to peroxisome-proliferating agents will be compared. Then, we will examine DNA isolated from livers of similarly exposed animals for oxidative damage known to be associated with mutation and cancer under other circumstances. Once this basic hypothesis has been tested, we proposed to expand the knowledge of the effect of these agents on intracellular H2O2 metabolism beyond their peroxisome proliferation. The in vivo and in vitro effects of these compounds on generation of H2O2 by isolated peroxisomes, mitochondria and endoplasmic reticulum will be investigated. A detailed analysis of the in vivo and in vitro effects on enzymes that decompose H2O2, catalase and glutathione peroxidase, will be performed. Also, effects on glutathione and glutathione-requiring enzymes will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039545-02
Application #
3178648
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-12-01
Project End
1988-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Bennett, A M; Williams, G M (1993) Alteration of rat liver endoplasmic reticulum Ca(2+)-ATPase thiol integrity by ciprofibrate, a peroxisome proliferator. Biochem Pharmacol 45:2093-8
Bennett, A M; Williams, G M (1993) Calcium as a permissive factor but not an initiation factor in DNA synthesis induction in cultured rat hepatocytes by the peroxisome proliferator ciprofibrate. Biochem Pharmacol 46:2219-27
Budroe, J D; Umemura, T; Angeloff, K et al. (1992) Dose-response relationships of hepatic acyl-CoA oxidase and catalase activity and liver mitogenesis induced by the peroxisome proliferator ciprofibrate in C57BL/6N and BALB/c mice. Toxicol Appl Pharmacol 113:192-8
Bennett, A M; Williams, G M (1992) Reduction of rat liver endoplasmic reticulum Ca(2+)-ATPase activity and mobilization of hepatic intracellular calcium by ciprofibrate, a peroxisome proliferator. Biochem Pharmacol 43:595-605
Kahn, S M; Jiang, W; Culbertson, T A et al. (1991) Rapid and sensitive nonradioactive detection of mutant K-ras genes via 'enriched' PCR amplification. Oncogene 6:1079-83
Maruyama, H; Tanaka, T; Williams, G M (1990) Effects of the peroxisome proliferator di(2-ethylhexyl)phthalate on enzymes in rat liver and on carcinogen-induced liver altered foci in comparison to the promoter phenobarbital. Toxicol Pathol 18:257-67
Butler, E G; Ichida, T; Maruyama, H et al. (1990) Toxicological studies on a benzofurane derivative. II. Demonstration of peroxisome proliferation in rat liver. Toxicol Appl Pharmacol 106:500-8
Butler, E G; England, P J; Williams, G M (1988) Genetic differences in enzymes associated with peroxisome proliferation and hydrogen peroxide metabolism in inbred mouse strains. Carcinogenesis 9:1459-63
Butler, E G; Tanaka, T; Ichida, T et al. (1988) Induction of hepatic peroxisome proliferation in mice by lactofen, a diphenyl ether herbicide. Toxicol Appl Pharmacol 93:72-80
Williams, G M; Maruyama, H; Tanaka, T (1987) Lack of rapid initiating, promoting or sequential syncarcinogenic effects of di(2-ethylhexyl)phthalate in rat liver carcinogenesis. Carcinogenesis 8:875-80