Xu Ethan Yixun, Perlina Ally, Vu Heather, Troth Sean P, Brennan Richard J, Aslamkhan Amy G, Xu Qiuwei
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Chem Res Toxicol. 2008 Aug;21(8):1548-61. doi: 10.1021/tx800061w. Epub 2008 Jul 26.
In this study, approximately 40 endogenous metabolites were identified and quantified by (1)H NMR in urine samples from male rats dosed with two proximal tubule toxicants, cisplatin and gentamicin. The excreted amount of a majority of those metabolites in urine was found to be dose-dependent and exhibited a strong correlation with histopathology scores of overall proximal tubule damage. MetaCore pathway analysis software (GeneGo Inc.) was employed to identify nephrotoxicant-associated biochemical changes via an integrated quantitative analysis of both urine metabolomic and kidney transcriptomic profiles. Correlation analysis was applied to establish quantitative linkages between pairs of individual metabolite and gene transcript profiles in both cisplatin and gentamicin studies. This analysis revealed that cisplatin and gentamicin treatments were strongly linked to declines in mRNA transcripts for several luminal membrane transporters that handle each of the respective elevated urinary metabolites, such as glucose, amino acids, and monocarboxylic acids. The integrated pathway analysis performed on these studies indicates that cisplatin- or gentamicin-induced renal Fanconi-like syndromes manifested by glucosuria, hyperaminoaciduria, lactic aciduria, and ketonuria might be better explained by the reduction of functional proximal tubule transporters rather than by the perturbation of metabolic pathways inside kidney cells. Furthermore, this analysis suggests that renal transcription factors HNF1alpha, HNF1beta, and HIF-1 might be the central mediators of drug-induced kidney injury and adaptive response pathways.
在本研究中，通过氢核磁共振（¹H NMR）对雄性大鼠尿液样本中的约40种内源性代谢物进行了鉴定和定量分析，这些大鼠被给予了两种近端小管毒物，顺铂和庆大霉素。发现尿液中大多数这些代谢物的排泄量呈剂量依赖性，并且与近端小管整体损伤的组织病理学评分具有很强的相关性。使用MetaCore通路分析软件（GeneGo公司），通过对尿液代谢组学和肾脏转录组学图谱的综合定量分析，来识别与肾毒物相关的生化变化。在顺铂和庆大霉素研究中，均应用相关性分析来建立个体代谢物和基因转录图谱之间的定量联系。该分析表明，顺铂和庆大霉素处理与几种管腔膜转运蛋白的mRNA转录物下降密切相关，这些转运蛋白负责处理各自升高的尿液代谢物，如葡萄糖、氨基酸和单羧酸。对这些研究进行的综合通路分析表明，顺铂或庆大霉素诱导的以糖尿、高氨基酸尿、乳糖尿和酮尿为特征的肾范可尼样综合征，可能更好地由功能性近端小管转运蛋白的减少来解释，而不是由肾细胞内代谢途径的扰动来解释。此外，该分析表明，肾转录因子HNF1α、HNF1β和HIF-1可能是药物诱导的肾损伤和适应性反应途径的核心介质。
