In this renewal application, research is proposed to elucidate the toxicologic mechanism(s) for the liver carcinogenicity of certain peroxisome-proliferating agents (PPA). The dominant hypotherical mechanism, for which there is substantial supporting evidence, is that these agents increase cellular levels of H2O2 leading to macromolecular damage and cellular alteration. During the previous grant period, we were unable to obtain direct confirmation for this sequence, but further experiments are proposed to examine the hypothesis in a rigorous manner. Findings in the preceding research also lead us to consider additional mechanisms, which may operate independent of oxidative damage or in conjunction with it.
The specific aims for the contimued research are as follows: (1) Identify two genetically-defined groups of mice and a PPA most likely to show differences in PPA-induced tumorigenesis, assuming the H2O2 hypothesis to be true and delineate the dose-response effects of that PPA on tumorigenesis in those two groups; (2) Investigate PPA-induced oxidative damage on liver cell macromolecules and; (3) Investigate PPA-induced liver cell proliferation as a mechanistically important event in PPA carcinogenicity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Toxicology Subcommittee 2 (TOX)
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Institute for Cancer Prevention
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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