title: Drug-Metabolizing Activity, Protein and Gene Expression of UDP-Glucuronosyltransferases Are Significantly Altered in Hepatocellular Carcinoma Patients.
abstract: UDP-glucuronosyltransferases (UGTs), the most important enzymes in body detoxification and homeostasis maintaining, govern the glucuronidation reaction of various endogenous and environmental carcinogens. The metabolic function of UGTs can be severely influenced by hepatocellular carcinoma (HCC), the fifth prevalent and third malignant cancer worldwide. Particularly in China, HBV-positive HCC account for approximately 80% of HCC patients. But rare papers addressed the alteration on the metabolism of UGTs specific substrates, translational and transcriptional activity of UGTs in HBV-positive HCC patients. In present study, we choose the main UGT isoforms, UGT1As, UGT1A1, UGT1A9, UGT1A4 and UGT2B7, to determine the alterations of metabolic activity, protein and gene expression of UGTs in HBV-positive HCC. The corresponding specific substrates such as genistein, SN-38, tamoxifen, propofol and zidovudine were utilized respectively in UGTs metabolic activity determination. Furthermore, the plausible mechanism responsible for UGTs alterations was addressed by analyzing the protein and gene expressions in tumor and the adjacent normal tissues in HBV-positive HCC. The results revealed that in the tumor human liver microsomes (HLMs), either V(max) (maximum reaction rate, R(max) for UGT1A1) or the clearance rates (V(max)/K(m), Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were significant lower than those of in the adjacent normal HLMs. Subsequently, the relative protein and gene expressions of these isoforms were notably decreased in most of tumor tissues comparing with the adjacent normal tissues. More interestingly, in tumor tissues, the metabolic activity reduction ratio of each UGT isoform was closely related to its protein reduction ratio, indicating that decreasing protein level would contribute to the reduced metabolic function of UGTs in HBV-positive HCC. In summary, our study firstly determined the alteration of UGT function in HBV-positive HCC patients, which would provide an important insight for toxicity or efficacy determination of chemotherapeutic drugs, and even bring a new strategy for clinical regimen in the health cares for the relative patients.
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
authors.forename: Xiao-juan
authors.initials: XJ
authors.lastname: Peng
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China.
authors.forename: Xiao-xiao
authors.initials: XX
authors.lastname: Qi
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Fu-Yuan
authors.initials: FY
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), 999078, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, PR China.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Liu
mesh_terms: D000328:Adult; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019833:Genistein / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D015742:Propofol / Q000493:pharmacokinetics; D013629:Tamoxifen / Q000493:pharmacokinetics; D015215:Zidovudine / Q000493:pharmacokinetics
chemical_list: D013629:Tamoxifen; D015215:Zidovudine; D000077146:Irinotecan; D019833:Genistein; D014453:Glucuronosyltransferase; D002166:Camptothecin; D015742:Propofol