Metabolism and Genotoxicity of Mutagenic Noncarcinogens

Cunningham, M L.

Abstract

The purpose of the research in this laboratory is to investigate chemical and biochemical factors which account for 'false positive' mutagenic noncarcinogens. This investigation of nonconcordance between the short- term genotoxicity assays and the results of bioassays has determined that the mutagenic carcinogen-noncarcinogen pair 2,4-& 2,6-diaminotoluene (DAT) differ only in that the carcinogenic isomer produced a dose-related increase in cell proliferation in the liver whereas the noncarcinogen produced no increase in cell proliferation even at higher doses. Subsequent studies utilizing the incorporation of bromodeoxyuridine into newly synthesized DNA have demonstrated that the mutagenic noncarcinogen- carcinogen pair 1-& 2-nitropropane (NP) have a similar pattern of toxicity. That is, the hepatocarcinogenic isomer 2-NP produced a dose-related increase in cell proliferation in the liver yet the noncarcinogenic isomer 1-NP did not. These results suggest and further confirm a positive correlation between cell proliferation and carcinogenicity for these chemicals, irrespective of their mutagenicity. Future research will expand these findings with other chemical pairs, especially mutagenic carcinogen- noncarcinogen pairs whenever possible to further evaluate the role of cell proliferation in experimental carcinogenesis.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES021119-02
• Application #: 3876869
• Support Year: 2
• Fiscal Year: 1990

Institution

• Name: National Institute of Environmental Health Sciences
• Country: United States

Publications

Bhave, Vishakha S; Donthamsetty, Shashikiran; Latendresse, John R et al. (2011) Secretory phospholipase A?-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2. Toxicol Appl Pharmacol 251:173-80

Fostel, Jennifer M; Burgoon, Lyle; Zwickl, Craig et al. (2007) Toward a checklist for exchange and interpretation of data from a toxicology study. Toxicol Sci 99:26-34

Woods, Courtney G; Burns, Amanda M; Maki, Akira et al. (2007) Sustained formation of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone radical adducts in mouse liver by peroxisome proliferators is dependent upon peroxisome proliferator-activated receptor-alpha, but not NADPH oxidase. Free Radic Biol Med 42:335-42

Woods, Courtney G; Burns, Amanda M; Bradford, Blair U et al. (2007) WY-14,643 induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase. Toxicol Sci 98:366-74

Cunningham, Michael L (2006) Putting the fun into functional toxicogenomics. Toxicol Sci 92:347-8

Dunnick, J; Blackshear, P; Kissling, G et al. (2006) Critical pathways in heart function: bis(2-chloroethoxy)methane-induced heart gene transcript change in F344 rats. Toxicol Pathol 34:348-56

Powell, Christine L; Kosyk, Oksana; Ross, Pamela K et al. (2006) Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver. Toxicol Sci 93:213-22

Coecke, Sandra; Ahr, Hans; Blaauboer, Bas J et al. (2006) Metabolism: a bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM workshop 54. Altern Lab Anim 34:49-84

Rusyn, Ivan; Peters, Jeffrey M; Cunningham, Michael L (2006) Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol 36:459-79

Raimondi, Sara; Boffetta, Paolo; Anttila, Sisko et al. (2005) Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res 592:45-57