J Prote Res：人体的“超级生物”观念促进非人类细胞药物开发

人们越来越多地认识到一个典型的人身上只有一小部分细胞和基因是人的。面对这种情况，科学家正在提出一种革命性的方法，用于开发针对人的人类和非人类组成部分的新药和疗法。这就是发表在美国化学学会（ACS）的《蛋白质组研究杂志》（Journal of Proteome Research）的一篇论文的主题，它综述了与该主题有关的将近100个研究的工作。

Liping Zhao、Jeremy K. Nicholson及其同事解释说，人类由于他们的身体含有10%的人类细胞和主要生活在肠道中的90%的微生物而被称为“超级生物”。这里的“超级”的意思是“超越”。科学家因此把人们视为庞大的生态系统，在其中人类、细菌、真菌和其他细胞相互作用。例如，微生物释放物质从而确定人类基因是否打开或关闭，并且影响免疫系统对疾病的防御。而人体微生物群随着饮食、药物和其他因素的变化而变化。

“这种人体的超级生物观念提供了具有临床相关性的全身层次上的一个管理人类健康的全新系统概念，”这组作者说。他们把它称为“现代医学的最显著的范式转移之一”。这篇论文描述了这种革命性的变化如何促进了一种称为“功能元基因组学”的促进新药开发的方法的出现。它打开了用针对人体的非人类细胞的药物和其他物质维持健康和治疗疾病的可能性。这篇论文指出，传统中药的许多物质可能是以这种方式起作用的。

doi:10.1021/pr201161f
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Pharmacometabonomic Investigation of Dynamic Metabolic Phenotypes Associated with Variability in Response to Galactosamine Hepatotoxicity

Muireann Coen*†, Françoise Goldfain-Blanc‡, Gaëlle Rolland-Valognes§, Bernard Walther, Donald G. Robertson, Elaine Holmes†, John C. Lindon†, and Jeremy K. Nicholson*†

Galactosamine (galN) is widely used as an in vivo model of acute liver injury. We have applied an integrative approach, combining histopathology, clinical chemistry, cytokine analysis, and nuclear magnetic resonance (NMR) spectroscopic metabolic profiling of biofluids and tissues, to study variability in response to galactosamine following successive dosing. On re-challenge with galN, primary non-responders displayed galN-induced hepatotoxicity (induced response), whereas primary responders exhibited a less marked response (adaptive response). A systems-level metabonomic approach enabled simultaneous characterization of the xenobiotic and endogenous metabolic perturbations associated with the different response phenotypes. Elevated serum cytokines were identified and correlated with hepatic metabolic profiles to further investigate the inflammatory response to galN. The presence of urinary N-acetylglucosamine (glcNAc) correlated with toxicological outcome and reflected the dynamic shift from a resistant to a sensitive phenotype (induced response). In addition, the urinary level of glcNAc and hepatic level of UDP-N-acetylhexosamines reflected an adaptive response to galN. The unique observation of galN-pyrazines and altered gut microbial metabolites in fecal profiles of non-responders suggested that gut microfloral metabolism was associated with toxic outcome. Pharmacometabonomic modeling of predose urinary and fecal NMR spectroscopic profiles revealed a diverse panel of metabolites that classified the dynamic shift between a resistant and sensitive phenotype. This integrative pharmacometabonomic approach has been demonstrated for a model toxin; however, it is equally applicable to xenobiotic interventions that are associated with wide variation in efficacy or toxicity and, in particular, for prediction of susceptibility to toxicity.