Medical Research Service, VA Pittsburgh Healthcare System Pittsburgh, PA, USA ; Department of Psychiatry, University of Pittsburgh School of Medicine Pittsburgh, PA, USA ; Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, PA, USA.
Front Cell Neurosci. 2013 Jun 11;7:90. doi: 10.3389/fncel.2013.00090. eCollection 2013.
Schizophrenia (SZ) is a biochemically complex disorder characterized by widespread defects in multiple metabolic pathways whose dynamic interactions, until recently, have been difficult to examine. Rather, evidence for these alterations has been collected piecemeal, limiting the potential to inform our understanding of the interactions amongst relevant biochemical pathways. We herein review perturbations in purine and neurotransmitter metabolism observed in early SZ using a metabolomic approach. Purine catabolism is an underappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. We have observed a homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with SZ (FENNS). Precursor and product relationships within purine pathways are tightly correlated. Although some of these correlations persist across disease or medication status, others appear to be lost among FENNS suggesting that steady formation of the antioxidant uric acid (UA) via purine catabolism is altered early in the course of illness. As is the case for within-pathway correlations, there are also significant cross-pathway correlations between respective purine and tryptophan (TRP) pathway metabolites. By contrast, purine metabolites show significant cross-pathway correlation only with tyrosine, and not with its metabolites. Furthermore, several purine metabolites (UA, guanosine, or xanthine) are each significantly correlated with 5-hydroxyindoleacetic acid (5-HIAA) in healthy controls, but not in FENNS at baseline or 4-week after antipsychotic treatment. Taken together, the above findings suggest that purine catabolism strongly associates with the TRP pathways leading to serotonin (5-hydroxytryptamine, 5-HT) and kynurenine metabolites. The lack of a significant correlation between purine metabolites and 5-HIAA, suggests alterations in key 5-HT pathways that may both be modified by and contribute to oxidative stress via purine catabolism in FENNS.
精神分裂症（SZ）是一种生化复杂的疾病，其特征是多种代谢途径广泛存在缺陷，这些途径的动态相互作用在最近之前一直难以研究。相反，这些改变的证据是零碎收集的，限制了告知我们对相关生化途径相互作用的理解的潜力。我们在此使用代谢组学方法综述了早期精神分裂症中观察到的嘌呤和神经递质代谢的扰动。嘌呤分解代谢是线粒体对氧化应激的稳态反应中被低估但重要的组成部分。我们观察到初发未经神经阻滞剂治疗的精神分裂症患者（FENNS）嘌呤分解代谢的稳态失衡。嘌呤途径中的前体和产物关系密切相关。尽管这些相关性中的一些在疾病或药物状态中持续存在，但其他相关性似乎在 FENNS 中丢失，表明通过嘌呤分解代谢稳定形成抗氧化剂尿酸（UA）在疾病过程的早期就发生了改变。与途径内相关性一样，嘌呤和色氨酸（TRP）途径代谢物之间也存在显著的跨途径相关性。相比之下，嘌呤代谢物仅与酪氨酸而不是其代谢物具有显著的跨途径相关性。此外，在健康对照组中，几种嘌呤代谢物（UA、鸟苷或黄嘌呤）与 5-羟吲哚乙酸（5-HIAA）均呈显著相关，但在 FENNS 基线或抗精神病药物治疗 4 周后均不相关。综上所述，上述发现表明嘌呤分解代谢与导致血清素（5-羟色胺，5-HT）和犬尿氨酸代谢物的 TRP 途径强烈相关。嘌呤代谢物与 5-HIAA 之间没有显著相关性，这表明在 FENNS 中，关键的 5-HT 途径可能发生改变，并且可能通过嘌呤分解代谢来修饰和导致氧化应激。
