Screening Of Multi-tissue Endogenous Susceptibility Markers For Capecitabine Related Hepatotoxicity In Colorectal Cancer

Objective:Screening endogenous susceptibility markers related to capecitabine related hepatotoxicity from normal colorectal tissue,blood and urine of Chinese patients with colorectal cancer(CRC),so as to explore the mechanism of capecitabine related hepatotoxicity susceptibility and establish a prediction model.Methods:In an observational clinical trial,CRC patients in China who required capecitabine for postoperative adjuvant chemotherapy were enrolled.Collecting samples(normal colorectal tissues,plasma and urine)from CRC patients prior to surgery(before capecitabine administration).According to CTCAE4.0 standard,the occurrence of hepatotoxicity during chemotherapy was recorded.The samples were divided into two groups with and without hepatotoxicity.The metabolic profiles of 63 CRC patients were analyzed using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS).After excluding the influence of mixed factors on the data,endogenous susceptible metabolites related to hepatotoxicity were obtained by difference analysis.Multi-tissue integration analysis was performed by MOFA to determine the contribution weight of each compound to hepatotoxicity susceptibility.On the basis of this,on the one hand,by combining pathway enrichment analysis,correlation analysis,and literature research,to explore the susceptibility of capecitabine chemotherapy liver toxicity mechanism,at the same time,through the analysis of the random forest multiariable logistic regression analysis,further screening of capecitabine chemotherapy hepatotoxicity endogenous risk markers,and verify the prediction model is established accordingly.Results:In this study,biomarkers associated with hepatotoxicity in capecitabine chemotherapy were identified by untargeted metabolomics analysis of endogenous metabolites in normal colorectal tissue,plasma,and urine samples.In normal colorectal tissues,a series of diagnostic markers for hepatotoxicity were found,which included BHIB,Riboflavin-5-phosphate,Adenine,Adenosine,Hexadecan-1-ol and Spermidine.The ROC curve shows AUC is 0.940.In plasma,a series of diagnostic markers for hepatotoxicity were found,which included Palmitic acid,LXA4,S1 P,Cer,PE(36:1)and Galactose.The ROC curve shows AUC is 0.901.In urine a series of diagnostic markers for hepatotoxicity were found,which included PA,1-Deoxy-D-xylulose,Indan-1-ol,N(6)-Methyllysine Dihydrocaffeic acid3-O-glucuronide and 1-Deoxy-D-xylulose.The ROC curve shows AUC is 0.989.Conclusion:Disturbance of polyamine metabolism,lipid metabolism and purine metabolism associated with low PA content are endogenous predisposing factors of chemotherapeutic hepatotoxicity induced by capecitabine.The decreased cell repair function reflected by endogenous metabolites is the endogenous susceptibility mechanism of capecitabine chemotherapy hepatotoxicity.