Article pubs.acs.org/crt
Early Metabolome Profiling and Prognostic Value in ParaquatPoisoned Patients: Based on Ultraperformance Liquid Chromatography Coupled To Quadrupole Time-of-Flight Mass Spectrometry Lufeng Hu,† Guangliang Hong,‡ Yahui Tang,‡ Xianqin Wang,§ Congcong Wen,§ Feiyan Lin,∥ and Zhongqiu Lu*,‡ †
Department of Pharmacy, The First Affliated Hospital of Wenzhou Medical University, Wenzhou 325000, China Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China § Analytical and Testing Center of Wenzhou Medical University, Wenzhou 325035, China ∥ Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China ‡
S Supporting Information *
ABSTRACT: Paraquat (PQ) has caused countless deaths throughout the world. There remains no effective treatment for PQ poisoning. Here we study the blood metabolome of PQ-poisoned patients using ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). Patients were divided into groups according to blood PQ concentration. Healthy subjects served as controls. Metabolic features were statistically analyzed using multivariate pattern-recognition techniques to identify the most important metabolites. Selected metabolites were further compared with a series of clinical indexes to assess the prognostic value. PQ-poisoned patients showed substantial differences compared with healthy subjects. Based on variable of importance in the project (VIP) values and statistical analysis, 17 metabolites were selected and identified. These metabolites well-classified low PQ-poisoned patients, high PQ-poisoned patients, and healthy subjects, which was better than that of a complete blood count (CBC). Among the 17 metabolites, 20:3/18:1-PC (PC), LPA (0:0/16:0) (LPA), 19-oxo-deoxycorticosterone (19-oxo-DOC), and eicosapentaenoic acid (EPA) had prognostic value. In particular, EPA was the most sensitive one. Besides, the levels of EPA was correlated with LPA and 19-oxo-DOC. If EPA was excessively consumed, then prognosis was poor. In conclusion, the serum metabolome is substantially perturbed by PQ poisoning. EPA is the most important biomarker in early PQ poisoning.
1. INTRODUCTION
Mortality due to PQ poisoning remains high. When PQ serum concentration is >5000 ng/mL, survival drops to zero.14 Serum PQ concentration correlates with prognosis.14−16 However, there has been no intensive study focused on the metabolic changes and mechanisms of PQ poisoning in patients with varying serum PQ concentrations. Furthermore, no biomarker has been identified. In this study, we investigated early serum metabolic changes in PQ-poisoned patients using ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). Patients were divided into two groups according to serum PQ concentration, and metabolomic data were analyzed by using pattern recognition techniques to identify metabolic features. The results were comprehensively compared with routine clinical tests to assess prognostic value.
Paraquat (PQ; 1,1-dimethyl-4,4-bipyridinium dichloride), a widely used worldwide quaternary ammonium herbicide, works by targeting photosystem I and transferring electrons to molecular oxygen to inhibit photosynthesis.1 Although PQ is safe in agricultural production, it causes severe toxicity in humans. To date, there are thousands of deaths attributed to PQ poisoning, particularly in developing countries.2−4 In order to improve the treatment of PQ poisoning, various clinical and basic studies have been carried out. According to a pathogenesis study,5 oxidative stress plays a important role in PQ-stimulated multiple organ injury.6 Increased levels of reactive oxygen species induce nonselective oxidation of lipids, proteins, and nucleic acids. This in turn leads to direct cellular and tissue damage.7−9 Clinical treatment studies show that gastric lavage, blood purification, antioxidants, cyclophosphamide, corticosteroids, and some traditional Chinese medicines were useful in PQ treatment.10−12 In particular, early hemoperfusion (≤6 h) improves survival rates.11,13 © 2017 American Chemical Society
Received: August 26, 2017 Published: November 3, 2017 2151
DOI: 10.1021/acs.chemrestox.7b00240 Chem. Res. Toxicol. 2017, 30, 2151−2158
Article
Chemical Research in Toxicology Table 1. Clinical Characteristics of PQ-Poisoned Patients and Healthy Subject (Mean ± SD) Characteristics Age Male/Female White blood cell Percentage of neutrophilic granulocyte Percentage of monocyte Percentage of leukomonocyte Absolute value of neutrophilic granulocyte Absolute value of monocyte Absolute value of leukomonocyte Red blood cell Hemoglobin Haematocrit Mean corpuscular volume Mean corpuscular hemoglobin Mean corpuscular hemoglobin concentration Red cell volume distribution width Blood platelet Thrombocytocrit Mean platelet volume Platelet distribution width
Low PQ group (n = 20) 38.80 11/9 11.65 0.88 0.02 0.10 10.28 0.32 1.06 4.31 130.70 0.39 91.50 30.44 332.70 13.15 140.95 0.13 9.23 16.49
± 16.16 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
High PQ group (n = 37) 39.73 14/7 22.83 0.91 0.04 0.05 21.08 0.83 1.04 4.50 131.95 0.39 87.45 29.41 336.00 14.17 169.91 1.65 8.75 16.75
5.90 0.08 0.02 0.07 5.64 0.39 0.92 0.68 17.29 0.06 3.54 1.76 15.14 0.73 71.10 0.07 1.72 1.51
± 18.04 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
10.52 0.05 0.03 0.03 10.27 0.61 0.54 0.65 20.85 0.06 7.98 3.06 10.40 2.41 87.74 8.97 1.79 1.05
healthy group (n = 29) 35.04 15/14 5.70 0.54 0.07 0.37 2.93 0.42 2.06 4.95 151.04 0.44 88.63 30.55 345.14 12.59 216.93 0.24 10.96 13.24
± 4.28 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
1.22 0.08 0.01 0.07 1.02 0.11 0.53 0.41 13.79 0.04 5.01 1.45 14.15 0.70 38.67 0.04 0.93 1.98
P 0.418 −
