Hepatic expression of UGT enzymes and implications in pharmacokinetic variations in Asians during chemotherapy

Abstract

14089 Background: The objective of this study was to screen the promoter and relevant coding regions in the UGT1A1 and UGT1A9 genes and genotypically quantitate expression of these genes in hepatic tissues obtained from Asian cancer patients undergoing hepatectomy. Methods: Non-cancerous Asian hepatic tissues (Chinese: N=36; Malay: N=1; Indian: N=3) were obtained from the institution’s central tissue repository bank. Messenger RNA was isolated from each tissue sample and reverse transcribed to cDNA followed by real time PCR experiments. Results from these gene expression experiments were normalized against GAPDH transcripts. DNA was also extracted from the hepatocytes, screened for variations in the promoter regions (UGT1A1*60, g.3140G>A and UGT1A1*28) and exon 1 (UGT1A1*6) of the UGT1A1 and UGT1A9 (UGT1A9*22, I399C>T) genes. Results: Large interindividual variations were observed in the hepatic expression pattern of UGT1A1 and UGT1A9 mRNA with respect to the different polymorphic variants. There was no significant association between hepatic expression of UGT1A1 mRNA and UGT1A1*60, g-3140G>A and *6 genotypes (P>0.05 in each case). The median expression level of UGT1A1 mRNA was approximately 2-fold higher in liver tissues harboring UGT1A1 6/6 (reference) genotype (N=27, median = 0.478; range: 0.065 to 3.125) compared to the heterozygous 6/7 genotype (N=9, median = 0.254; range: 0.042 to 1.894; P=0.77). The median expression levels of UGT1A9 mRNA were approximately 3-fold higher in liver tissues harboring I399CC genotype (N=3, median = 2.735; range: 0.702 to 3.375) when compared with the homozygous variant TT genotype (N=8, median = 0.973; range: 0.652 to 4.155; P=0.88). Conclusions: The results showed that polymorphisms in the UGT1A genes may influence the expression pattern of the respective proteins and could contribute to the high degree of interpatient variability in the glucuronidation dependent metabolism and elimination of chemotherapeutic agents in Asian cancer patients. No significant financial relationships to disclose.