Bouchard L, Castonguay A
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Drug Metab Dispos. 1993 Mar-Apr;21(2):293-8.
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)
我们之前的研究表明，非甾体抗炎药舒林酸可抑制烟草特异性致癌物4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮（NNK）诱导的肺癌发生。在本文中，我们描述了舒林酸及其硫化物代谢物的代谢情况，以及它们对体外培养肺组织中NNK代谢的抑制作用。舒林酸氧化为砜代谢物的程度与时间（0至16小时）和浓度（0至1 mM）呈线性关系。硫化物代谢物氧化为舒林酸的速度比舒林酸氧化为砜代谢物的速度更快。肺组织中2.36 microM NNK的三种代谢途径为α-碳羟基化、吡啶N-氧化和羰基还原。100 microM舒林酸对α-碳羟基化和吡啶N-氧化没有显著抑制作用。相比之下，100 microM硫化物代谢物使总体α-碳羟基化受到35%的抑制（p < 0.001），吡啶N-氧化受到32%的抑制（p < 0.001）。硫化物对羰基还原没有影响。我们得出结论，硫化物与NNK竞争相同的单加氧酶酶系统。我们比较了5种非甾体抗炎药对2.36 microM NNK代谢的抑制程度。舒林酸效果最差，萘普生和布洛芬效果最好。萘普生和布洛芬抑制NNK的α-碳羟基化达72%。吲哚美辛和吡罗昔康对该途径的抑制率分别为32%和28%。舒林酸的抑制率（20%）无统计学意义。这些结果表明，非甾体抗炎药可抑制靶组织中致癌物的活化。（摘要截短至250字）
