Formation of acrolein-derived 2'-deoxyadenosine adduct in an iron-induced carcinogenesis model.
Acrolein is a representative carcinogenic aldehyde found ubiquitously in the environment and formed endogenously through oxidation reactions, such as lipid peroxidation and myeloperoxidase-catalyzed amino acid oxidation. It shows facile reactivity toward DNA to form an exocyclic DNA adduct. To verify the formation of acrolein-derived DNA adduct under oxidative stress in vivo, we raised a novel monoclonal antibody (mAb21) against the acrolein-modified DNA and found that the antibody most significantly recognized an acrolein-modified 2' -deoxyadenosine. On the basis of chemical and spectroscopic evidence, the major antigenic product of mAb21 was the 1,N6-propano-2' -deoxyadenosine adduct. The exposure of rat liver epithelial RL34 cells to acrolein resulted in a significant accumulation of the acrolein-2' -deoxyadenosine adduct in the nuclei. Formation of this adduct under oxidative stress in vivo was immunohistochemically examined in rats exposed to ferric nitrilotriacetate, a carcinogenic iron chelate that specifically induces oxidative stress in the kidneys of rodents. It was observed that the acrolein-2' -deoxyadenosine adduct was formed in the nuclei of the proximal tubular cells, the target cells of this carcinogenesis model. The same cells were stained with a monoclonal antibody 5F6 that recognizes an acrolein-lysine adduct, by which cytosolic accumulation of acrolein-modified proteins appeared. Similar results were also obtained from myeloperoxidase knockout mice exposed to the iron complex, suggesting that the myeloperoxidase-catalyzed oxidation system might not be essential for the generation of acrolein in this experimental animal carcinogenesis model. The data obtained in this study suggest that the formation of a carcinogenic aldehyde through lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.
Kawai
Yoshichika
Y
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
Furuhata
Atsunori
A
Toyokuni
Shinya
S
Aratani
Yasuaki
Y
Uchida
Koji
K
D000171:Acrolein / Q000737:chemistry*; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D003839:Deoxyadenosines / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007477:Ions; D007501:Iron / Q000737:chemistry / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008956:Models, Chemical; D009369:Neoplasms / Q000139:chemically induced*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D009195:Peroxidase / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013912:Threonine / Q000737:chemistry; D013950:Thymus Gland / Q000378:metabolism; D013997:Time Factors
D000447:Aldehydes; D000911:Antibodies, Monoclonal; D018736:DNA Adducts; D003839:Deoxyadenosines; D007477:Ions; C064049:1,N(6)-propanodeoxyadenosine; D013912:Threonine; D000171:Acrolein; D007501:Iron; D009195:Peroxidase; D008239:Lysine; C058118:2'-deoxyadenosine; D010100:Oxygen