Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W Markham St, Little Rock, AR, 72205, United States.
Department of Pathology and Immunology, 660 S Euclid Ave, Washington University, St. Louis, MO, 63130, United States.
Toxicology. 2020 Jul;440:152478. doi: 10.1016/j.tox.2020.152478. Epub 2020 May 11.
Thiazoles are biologically active aromatic heterocyclic rings occurring frequently in natural products and drugs. These molecules undergo typically harmless elimination; however, a hepatotoxic response can occur due to multistep bioactivation of the thiazole to generate a reactive thioamide. A basis for those differences in outcomes remains unknown. A textbook example is the high hepatotoxicity observed for sudoxicam in contrast to the relative safe use and marketability of meloxicam, which differs in structure from sudoxicam by the addition of a single methyl group. Both drugs undergo bioactivation, but meloxicam exhibits an additional detoxification pathway due to hydroxylation of the methyl group. We hypothesized that thiazole bioactivation efficiency is similar between sudoxicam and meloxicam due to the methyl group being a weak electron donator, and thus, the relevance of bioactivation depends on the competing detoxification pathway. For a rapid analysis, we modeled epoxidation of sudoxicam derivatives to investigate the impact of substituents on thiazole bioactivation. As expected, electron donating groups increased the likelihood for epoxidation with a minimal effect for the methyl group, but model predictions did not extrapolate well among all types of substituents. Through analytical methods, we measured steady-state kinetics for metabolic bioactivation of sudoxicam and meloxicam by human liver microsomes. Sudoxicam bioactivation was 6-fold more efficient than that for meloxicam, yet meloxicam showed a 6-fold higher efficiency of detoxification than bioactivation. Overall, sudoxicam bioactivation was 15-fold more likely than meloxicam considering all metabolic clearance pathways. Kinetic differences likely arise from different enzymes catalyzing respective metabolic pathways based on phenotyping studies. Rather than simply providing an alternative detoxification pathway, the meloxicam methyl group suppressed the bioactivation reaction. These findings indicate the impact of thiazole substituents on bioactivation is more complex than previously thought and likely contributes to the unpredictability of their toxic potential.
噻唑是生物活性的芳香杂环，经常出现在天然产物和药物中。这些分子通常会发生无害的消除；然而，由于噻唑的多步生物活化生成反应性硫代酰胺，可能会发生肝毒性反应。这些结果差异的基础尚不清楚。一个典型的例子是，与结构上仅差一个甲基的美洛昔康相比，昔布类药物中的舒多昔康具有较高的肝毒性。这两种药物都经历了生物活化，但美洛昔康由于甲基的羟化而表现出额外的解毒途径。我们假设，由于甲基是一个较弱的供电子体，舒多昔康和美洛昔康的噻唑生物活化效率相似，因此，生物活化的相关性取决于竞争的解毒途径。为了快速分析，我们模拟了舒多昔康衍生物的环氧化作用，以研究取代基对噻唑生物活化的影响。正如预期的那样，供电子基团增加了环氧化的可能性，而对甲基的影响最小，但模型预测并不能很好地外推到所有类型的取代基。通过分析方法，我们测量了人肝微粒体中舒多昔康和美洛昔康代谢生物活化的稳态动力学。舒多昔康的生物活化效率比美洛昔康高 6 倍，但美洛昔康的解毒效率比生物活化高 6 倍。总的来说，考虑到所有代谢清除途径，舒多昔康的生物活化比美洛昔康更有可能发生 15 倍。基于表型研究，这种动力学差异可能是由于不同的酶催化各自的代谢途径所致。美洛昔康的甲基基团不仅提供了一种替代解毒途径，而且抑制了生物活化反应。这些发现表明，噻唑取代基对生物活化的影响比之前认为的更为复杂，可能导致其毒性潜力的不可预测性。
