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 Vmax (maximum reaction rate, Rmax for UGT1A1) or the clearance rates (Vmax/Km, 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.

Deregulation of the Genes that Are Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Hepatocellular Carcinoma

“…3C). We also show UGT2B7 downregulation in HCC, a finding that was recently reported by others (Lu et al, 2015;Yan et al, 2015a). Previous studies have also reported downregulation of three other UGTs (1A1, 1A4, and 1A9) in HCC (Lu et al, 2015;Yan et al, 2015a).…”

Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp

“…The measured UGT2B7 activity in ALF rats was only approximately 70% of that in the control rats, in agreement with the decrease in protein expression of hepatic UGT2B7. These results were consistent with the findings in patients with liver disease [49,50] . The intestinal metabolism of AZT was also taken into consideration because UGT2B7 is also expressed in the intestine [51] , but the formation of GAZT in intestinal microsomes was not detected.…”

Genetic Association of Drug Response to Erlotinib in Chinese Advanced Non-small Cell Lung Cancer Patients

“…Few previous studies have investigated UGT3A1 variants in NSCLC. However, a recent study found that the UGT3A gene family catalyze biotransformation of endogenous and environmental carcinogens including drugs (Lu et al, 2015 ). Additionally, UGT3A1 differentiated primate species by participation in sugar conjugation during metabolism and elimination of lipophilic metabolites and exogenous chemicals (Meech and Mackenzie, 2010 ).…”