The Impact of UGT1A1 Genetic Variability on Enzyme Expression in Liver Pathology

Background: Glucuronidation is a major phase II biotransformation reaction responsible for the inactivation and elimination of endogenous compounds and pharmaceuticals. This process is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family, among which UGT1A1 is the most extensively studied. UGT1A1 plays a critical role in the metabolism of numerous drugs and is essential for bilirubin glucuronidation. Due to this specific function, it has significant clinical relevance, as impaired enzyme activity resulting from genetic polymorphisms or mutations can lead to the accumulation of unconjugated bilirubin in the bloodstream. This study aimed to evaluate the association between the UGT1A1*28 allele and the gene expression and protein levels in human liver tissue, in relation to different liver diseases. Methods: Liver tissues were obtained from patients with various liver pathologies and the control group consisted of tissues showing no pathological symptoms. A total of 143 patients were included in the study. Pyrosequencing was used to analyze PCR products for the UGT1A1*28 polymorphism (variable number of TA repeats in the TATA sequence of the promoter). Results: In both the control and study groups, UGT1A1 gene expression at the mRNA level and protein concentration in liver tissue decreased with the increasing number of UGT1A1*28 alleles. The association between UGT1A1 genotype and mRNA/protein content was most pronounced in HCV and AIH, and slightly weaker in the ALK and PBC groups. The significant association between UGT1A1*28 allele and bilirubin concentration was observed in control group but not in liver pathology. Conclusions: The UGT1A1*28 polymorphism is associated with reduced hepatic mRNA and protein abundance in patients with liver disease. However, the significance of this observation for the metabolism of the enzyme substrates should be further investigated.