Conclusion
These results suggest that UGT2B17 and UGT2B10 play key roles in the glucuronidation of 3HC in the human liver and that functional polymorphisms in UGT2B17 and UGT2B10 are associated with significantly reduced glucuronidation activities against 3HC.
Methods
In the present study, human liver microsomes (HLM), eight UGT1A and six UGT2B enzymes were screened for activity against 3HC.
Results
UGT2B17 exhibited the highest O-glucuronidation activity, exhibiting a four-fold lower (P<0.005) KM (8.3 mmol/l) compared with that observed for UGTs 1A9 (35 mmol/l) or 2B7 (31 mmol/l) and a KM smaller compared with that observed for human liver microsomes (HLM; 26 mmol/l). The KM for 3HC-O-Gluc formation was 3.1-fold lower (P<0.0005) in HLM from male participants exhibiting the wild-type genotype UGT2B17 (*1/*1) compared with that in HLM from participants homozygous for the UGT2B17 deletion genotype [UGT2B17 (*2/*2)]. Both UGTs 2B10 and 1A4 exhibited 3HC-N-Gluc formation activity, with UGT2B10 exhibiting a four-fold lower (P<0.05) KM (13 mmol/l) compared with that observed for UGT1A4 (57 mmol/l) and, which was similar to the KM observed in HLM (14 mmol/l). There was 91 (P<0.0001) and 39% (P<0.001) decreases in the 3HC-N-Gluc formation activities in HLM from participants with the UGT2B10 (*2/*2) and UGT2B10 (*1/*2) genotypes, respectively, compared with that of HLM from participants with the wild-type UGT2B10 (*1/*1) genotype.