Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert's syndrome

Abstract

Background/Aims: UDP-glucuronosyltransferases (UGTs) are important enzymes involved in glucuronidation of various exogenous and endogenous compounds. Studies were undertaken on the variability of three UGT enzyme activities in human livers. Enzyme activities were associated with genetic polymorphisms in UGT1A1 ( UGT1A1*28) and UGT1A6 ( UGT1A6*2). UGT1A1*28 is associated with Gilbert's syndrome, a deficiency in glucuronidation of bilirubin leading to mild hyperbilirubinemia, whereas UGT1A6*2 may result in low glucuronidation rates of several drugs. Methods: Enzyme activities and genetic polymorphisms were assessed in 39 human liver samples, and polymorphisms were also assessed in blood of 253 healthy controls. Results: Associations were found between UGT enzyme activities of bilirubin (B) and 4-nitrophenol (NP; r=0.47, P=0.0024), B and 4-methylumbelliferone (MUB; r=0.54, P=0.0003), and NP and MUB ( r=0.89, P<0.0001). In addition to the association between B-UGT enzyme activity and UGT1A1*28 ( r=0.45, P=0.0034) as reported earlier, an association between B-UGT and UGT1A6*2 ( r=0.43, P=0.007) was found. In 253 Dutch Caucasian controls, co-occurrence of UGT1A1*28 and UGT1A6*2 was found ( r=0.9, P<0.0001). Conclusions: Most patients with Gilbert's syndrome, in addition to their reduced B-UGT enzyme activity, may have abnormalities in the glucuronidation of aspirin or coumarin- and dopamine-derivatives, due to this combination of UGT1A1*28 and UGT1A6*2 genotypes.