Scott D, Reuben M, Zampighi G, Sachs G
Center for Ulcer Research and Education, VA West Los Angeles Medical Center.
Dig Dis Sci. 1990 Oct;35(10):1217-25. doi: 10.1007/BF01536410.
It has been claimed that in vitro digestion of in vivo DNA-labeled gastric mucosa is suitable for evaluation of genotoxic effects of drugs or chemicals. This method was then used to show that omeprazole (a novel antiulcer drug) was potentially genotoxic. In this study we have examined the method used and the interaction of omeprazole and its derivatives with purified DNA. The method was shown to enrich for dividing cells (6.92 +/- 0.693%, N = 43, 2-hr labeling) in the digest from the intact tissue and was therefore unsuitable for estimating unscheduled DNA synthesis in the gastric mucosa induced by chemicals or drugs including omeprazole. It was further shown that neither omeprazole or its acid-activated product, a cationic sulfenamide, were able to react with isolated purified DNA from either a prokaryote (E. coli) or a eukaryote (salmon sperm). Hence any conclusions using this method attributing acute genotoxic effects to any chemical are based on unrecognized artifacts of the technique and are unsound. In addition, these results negate the suggestion that omeprazole or its gastric metabolites are genotoxic.
有人声称，对体内DNA标记的胃黏膜进行体外消化，适用于评估药物或化学物质的遗传毒性作用。该方法随后被用于证明奥美拉唑（一种新型抗溃疡药物）具有潜在的遗传毒性。在本研究中，我们检查了所使用的方法以及奥美拉唑及其衍生物与纯化DNA的相互作用。结果表明，该方法能富集完整组织消化液中的分裂细胞（6.92±0.693%，N = 43，2小时标记），因此不适用于评估包括奥美拉唑在内的化学物质或药物诱导的胃黏膜非预定DNA合成。进一步研究表明，奥美拉唑及其酸激活产物（一种阳离子亚磺酰胺）均不能与原核生物（大肠杆菌）或真核生物（鲑鱼精子）分离的纯化DNA发生反应。因此，使用该方法将任何化学物质的急性遗传毒性作用归因于任何化学物质的结论，都是基于该技术未被认识到的假象，是不合理的。此外，这些结果否定了奥美拉唑或其胃代谢产物具有遗传毒性的说法。
