title: Inhibitory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mouse lung explants.
abstract: Our previous study showed that the nonsteroidal anti-inflammatory drug (NSAID), sulindac, inhibited lung tumorigenesis induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this paper, we describe the metabolism of sulindac and its sulfide metabolite and their inhibition of NNK metabolism in lung tissues cultured in vitro. The extent of oxidation of sulindac to the sulfone metabolite was linear with time (0 to 16 hr) and with concentration (0 to 1 mM). The sulfide metabolite was oxidized to sulindac more rapidly than sulindac was oxidized to the sulfone metabolite. The three metabolic pathways of 2.36 microM NNK in lung tissues are alpha-carbon hydroxylation, pyridine N-oxidation, and carbonyl reduction. alpha-Carbon hydroxylation and pyridine N-oxidation were not significantly inhibited by 100 microM sulindac. In contrast, 100 microM sulfide metabolite inhibited overall alpha-carbon hydroxylation by 35% (p < 0.001) and pyridine N-oxidation by 32% (p < 0.001). The sulfide had no effect on carbonyl reduction. We conclude that the sulfide is competing with NNK for the same monooxygenase enzyme system. We have compared the extent of inhibition of 2.36 microM NNK metabolism by 5 NSAIDs. Sulindac was the least effective and naproxen and ibuprofen were the most effective. Naproxen and ibuprofen inhibited the alpha-carbon hydroxylation of NNK by 72%. Inhibition of this pathway by indomethacin and piroxicam was 32% and 28%, respectively. Inhibition by sulindac (20%) was not statistically significant. These results indicate that NSAIDs inhibit carcinogen activation in target tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Bouchard
authors.forename: A
authors.initials: A
authors.lastname: Castonguay
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006900:Hydroxylation; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000378:metabolism*; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D010947:Plants, Toxic; D013056:Spectrophotometry, Ultraviolet; D013467:Sulindac / Q000493:pharmacokinetics / Q000494:pharmacology; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D009602:Nitrosamines; D013467:Sulindac; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone