alpha,beta-Unsaturated aldehydes (enals) are not only common environmental pollutants but they are also formed endogenously by metabolism of certain carcinogens and by lipid peroxidation. Enals are easily epoxidized to the epoxy aldehydes. Both enals and the epoxides modify DNA bases by forming the exocyclic adducts. The former yields propano adducts, whereas, the latter forms a variety of structurally unique adducts including etheno adducts. The expoxides are considerably more reactive toward DNA than the parent aldehydes. Consistent with these observations, the epoxide aldehydes are also more mutagenic and tumorigenic. The site-specific mutagenesis studies showed that exocyclic adducts are miscoding lesions. These adducts are detected by immunoassays and 32P-postlabeling in cultured cells and rodents exposed directly or metabolically to acrolein,crotonaldehyde and other related aldehydes. Exocyclic adducts are, therefore, likely to be involved in carcinogenesis. Recent studies showed that the propano and etheno adducts are present, at relatively high levels, in the tissue DNA of untreated rodents and humans. These results suggest that exocyclic adducts are formed from endogenous sources. We hypothesize that 1,N2- propanodeoxyguanosine adducts of acrelein and crotonaldehyde, 1,N2- ethenodeoxyguanosine, and 1,N6-ethenodeoxyadenosine are formed in tissue DNA by endogenous lipid peroxidation. To test this hypothesis we will: 1. study effects of lipid peroxidation on the formation of exocyclic adducts in DNA with hepatic microsomes and cultured hepatocytes; 2. examine effects of in vivo lipid peroxidation on levels and persistence of the exocyclic adducts in the liver DNA of rats; 3. establish specific in vivo epoxidation pathways by studying the formation of the substituted etheno adducts in rat liver DNA; 4. examine the interspecies and age-related differences in adduct levels; 5. examine effects of dietary fat on the formation of adducts in the DNA of rats; 6. study the roles of enal conjugates in DNA adduction and mutagenicity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043159-11
Application #
2007594
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1986-08-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Fu, Ying; Silverstein, Shana; McCutcheon, Justine N et al. (2018) An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice. Hepatology 67:159-170
Pan, Jishen; Sinclair, Elizabeth; Xuan, Zhuoli et al. (2016) Nucleotide excision repair deficiency increases levels of acrolein-derived cyclic DNA adduct and sensitizes cells to apoptosis induced by docosahexaenoic acid and acrolein. Mutat Res 789:33-8
Choudhury, Sujata; Dyba, Marcin; Pan, Jishen et al. (2013) Repair kinetics of acrolein- and (E)-4-hydroxy-2-nonenal-derived DNA adducts in human colon cell extracts. Mutat Res 751-752:15-23
Chung, Fung-Lung; Wu, Mona Y; Basudan, Ahmed et al. (2012) Regioselective formation of acrolein-derived cyclic 1,N(2)-propanodeoxyguanosine adducts mediated by amino acids, proteins, and cell lysates. Chem Res Toxicol 25:1921-8
Pan, Jishen; Awoyemi, Bisola; Xuan, Zhuoli et al. (2012) Detection of acrolein-derived cyclic DNA adducts in human cells by monoclonal antibodies. Chem Res Toxicol 25:2788-95
Nath, Raghu G; Wu, Mona Y; Emami, Armaghan et al. (2010) Effects of epigallocatechin gallate, L-ascorbic acid, alpha-tocopherol, and dihydrolipoic acid on the formation of deoxyguanosine adducts derived from lipid peroxidation. Nutr Cancer 62:622-9
Pan, Jishen; Keffer, Jessica; Emami, Armaghan et al. (2009) Acrolein-derived DNA adduct formation in human colon cancer cells: its role in apoptosis induction by docosahexaenoic acid. Chem Res Toxicol 22:798-806
Emami, Armaghan; Dyba, Marcin; Cheema, Amrita K et al. (2008) Detection of the acrolein-derived cyclic DNA adduct by a quantitative 32P-postlabeling/solid-phase extraction/HPLC method: blocking its artifact formation with glutathione. Anal Biochem 374:163-72
Pan, Jishen; Davis, Warren; Trushin, Neil et al. (2006) A solid-phase extraction/high-performance liquid chromatography-based (32)P-postlabeling method for detection of cyclic 1,N(2)-propanodeoxyguanosine adducts derived from enals. Anal Biochem 348:15-23
Chung, Fung-Lung; Komninou, Despina; Zhang, Lei et al. (2005) Glutathione depletion enhances the formation of endogenous cyclic DNA adducts derived from t-4-hydroxy-2-nonenal in rat liver. Chem Res Toxicol 18:24-7

Showing the most recent 10 out of 35 publications