Carcinogenesis, Vol. 22, No. 9, 1557-1560,
September 2001
© 2001 Oxford University Press
SHORT COMMUNICATION |
Cyclooxygenase-2, malondialdehyde and pyrimidopurinone adducts of deoxyguanosine in human colon cells
Oncology Department and
1 MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK,
2 Vanderbilt–Ingram Cancer Center, Nashville, TN 37232, USA and
3 Nestlé Research Center, Lausanne PO Box 44, CH-1000 Lausanne 26, Switzerland
Cyclooxygenases (COX) catalyse the oxygenation of arachidonic acid to prostaglandin (PG) endoperoxides. Activity of one of the COX isoforms, COX-2, results in production of prostaglandin E2 (PGE2) via the endoperoxide PGH2. COX-2 has been implicated in the pathogenesis of colorectal cancer. Malondialdehyde (MDA) is a mutagen produced by spontaneous and enzymatic breakdown of PGH2. MDA reacts with DNA to form adducts, predominantly the pyrimidopurinone adduct of deoxyguanosine (M1G). Here the hypothesis was tested that COX-2 activity in human colon cells results in formation of MDA and generation of M1G adducts. M1G was detected in basal cultures of human non-malignant colon epithelial (HCEC) and malignant SW48, SW480, HT29 and HCA-7 colon cells, at levels from 77 to 148 adducts/108 nucleotides. Only HCA-7 and HT29 cells expressed COX-2 protein. Levels of M1G correlated significantly (r = 0.98, P < 0.001) with those of intracellular MDA determined colorimetrically in the four malignant cell types, but neither parameter correlated with expression of COX-2 or PG biosynthesis. Induction of COX-2 expression by phorbol 12-myristate 13-acetate in HCEC cells increased PGE2 production 20-fold and MDA concentration 3-fold. Selective inhibition of COX-2 activity in HCA-7 cells by NS-398 significantly inhibited PGE2 production, but altered neither MDA nor M1G levels. Malondialdehyde treatment of HCEC cells resulted in a doubling of M1G levels. These results show for the first time in human colon cells that COX-2 activity is associated with formation of the endogenous mutagen, MDA. Moreover, they demonstrate the correlation between MDA concentration and M1G adduct levels in malignant cells.
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