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.