title: Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells.
abstract: Dietary heterocyclic aromatic amines (HCA) and polyunsaturated fatty acids (PUFA) are both believed to play a role in colon carcinogenesis, and are both substrate for the enzyme cyclooxygenase (COX). In HCA-7 cells, highly expressing isoform COX-2, we investigated the effects of PUFA on prostaglandin synthesis and DNA adduct formation by the HCA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Furthermore, we studied the role of COX, COX-2 in particular, and cytochrome P4501A2 (CYP1A2) by using the enzyme inhibitors indomethacin (IM), NS-398, and phenethyl isothiocyanate (PEITC), respectively. COX-mediated formation of prostaglandin E2 (PGE2) from linoleic acid (LA) showed that HCA-7 cells can convert LA into arachidonic acid (AA). Alternatively, eicosapentaenoic acid (EPA) was found to compete with AA for COX. Strongly decreased PGE2 levels by addition of IM demonstrated involvement of COX in PUFA metabolism. Both IM and NS-398 inhibited adduct formation by HCA to nearly the same extent, indicating involvement of COX-2 rather than COX-1, while CYP1A2 activity in HCA-7 cells was demonstrated by addition of PEITC. Overall, inhibiting effects were stronger for PhIP than for IQ. HCA-DNA adduct formation was stimulated by addition of PUFA, although high PUFA concentrations partly reduced this stimulating effect. Finally, similar effects for n-3 and n-6 fatty acids suggested that adduct formation may not be the crucial mechanism behind the differential effects of PUFA on colon carcinogenesis that have been described. These results show that COX, and COX-2 in particular, can play a substantial role in HCA activation, especially in extrahepatic tissues like the colon. Furthermore, the obvious interactions between PUFA and HCA in COX-2 expressing cancer cells may be important in modulating colorectal cancer risk.
authors.affiliation: Department of Health Risk Analysis and Toxicology, University of Maastricht, Maastricht, The Netherlands.
authors.forename: H J J
authors.initials: HJ
authors.lastname: Moonen
authors.forename: Y E M
authors.initials: YE
authors.lastname: Dommels
authors.forename: M
authors.initials: M
authors.lastname: van Zwam
authors.forename: M H M
authors.initials: MH
authors.lastname: van Herwijnen
authors.forename: J C S
authors.initials: JC
authors.lastname: Kleinjans
authors.forename: G M
authors.initials: GM
authors.lastname: Alink
authors.forename: T M C M
authors.initials: TM
authors.lastname: de Kok
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000588:Amines / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000588:Amines; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006571:Heterocyclic Compounds; D019787:Linoleic Acid; D019388:Cytochrome P-450 CYP1A2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone