Database screening as a strategy to identify endogenous candidate metabolites to probe and assess mitochondrial drug toxicity.
Database screening as a strategy to identify endogenous candidate metabolites to probe and assess mitochondrial drug toxicity.
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DOI：
10.1038/s41598-023-49443-0
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发表时间：
2023-12-12
影响因子：
4.6
通讯作者：
Rosania, Gus R.
中科院分区：
文献类型：
--
作者：
de la Rosa, Mery Vet George;Patel, Dipali;Mccann, Marc R.;Stringer, Kathleen A.;Rosania, Gus R.
药物不良反应 (ADR) 被认为是药物使用的固有风险，一些 ADR 与药物与线粒体的脱靶相互作用有关。反映线粒体功能的代谢物可能有助于识别存在线粒体毒性风险的患者。我们采用数据库策略来识别候选线粒体代谢物，这些代谢物在临床上可用于识别线粒体相关 ADR 风险增加的个体。这导致左旋肉碱被确定为候选线粒体代谢物。左旋肉碱、其乙酰化代谢物、乙酰肉碱和其他酰基肉碱是用于检测先天性代谢缺陷的线粒体生物标志物。我们假设，静脉注射左旋肉碱“挑战测试”引起的左旋肉碱处置变化可以通过引起左旋肉碱和/或乙酰肉碱血液水平的变化来识别线粒体相关的 ADR。为了验证这一假设，我们在小鼠模型中用氯法齐明 (CFZ) 诱导了线粒体药物毒性。 CFZ 治疗后，小鼠接受了左旋肉碱“挑战测试”。 CFZ 引起的体重变化与之前的工作一致，反映了 CFZ 引起的分解代谢。左旋肉碱以依赖 CFZ 治疗的方式引起全血乙酰肉碱浓度差异。这支持了数据库策略对于发现药物毒性候选代谢物生物标志物的有用性，并证实了左旋肉碱“挑战测试”作为识别药物相关毒理学表现的“探针”的潜力。
Adverse drug reactions (ADRs) are considered an inherent risk of medication use, and some ADRs have been associated with off-target drug interactions with mitochondria. Metabolites that reflect mitochondrial function may help identify patients at risk of mitochondrial toxicity. We employed a database strategy to identify candidate mitochondrial metabolites that could be clinically useful to identify individuals at increased risk of mitochondrial-related ADRs. This led to l-carnitine being identified as the candidate mitochondrial metabolite. l-carnitine, its acetylated metabolite, acetylcarnitine and other acylcarnitines are mitochondrial biomarkers used to detect inborn errors of metabolism. We hypothesized that changes in l-carnitine disposition, induced by a “challenge test” of intravenous l-carnitine, could identify mitochondrial-related ADRs by provoking variation in l-carnitine and/or acetylcarnitine blood levels. To test this hypothesis, we induced mitochondrial drug toxicity with clofazimine (CFZ) in a mouse model. Following CFZ treatment, mice received an l-carnitine “challenge test”. CFZ-induced changes in weight were consistent with previous work and reflect CFZ-induced catabolism. l-carnitine induced differences in whole blood acetylcarnitine concentrations in a manner that was dependent on CFZ treatment. This supports the usefulness of a database strategy for the discovery of candidate metabolite biomarkers of drug toxicity and substantiates the potential of the l-carnitine “challenge test” as a “probe” to identify drug-related toxicological manifestations.
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DOI：
10.1093/toxsci/kfy008
发表时间：
2018-03-01
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
--
作者：
Meyer JN;Hartman JH;Mello DF
通讯作者：
Mello DF
影响因子：
4.4
作者：
Ferreira GC;McKenna MC
通讯作者：
McKenna MC
影响因子：
4.1
作者：
McCann MR;George De la Rosa MV;Rosania GR;Stringer KA
通讯作者：
Stringer KA
影响因子：
4.9
作者：
Baik, Jason;Stringer, Kathleen A.;Rosania, Gus R.
通讯作者：
Rosania, Gus R.
影响因子：
5.2
作者：
Herst PM;Rowe MR;Carson GM;Berridge MV
通讯作者：
Berridge MV