Protein expression of various hepatic uridine 5'-diphosphate glucuronosyltransferase (UGT) enzymes and their inter-correlations: a meta-analysis

Avoiding cytochrome P450 (CYP) related drug interactions in the development of new drug candidates means that glucuronidation by uridine 5'-diphosphate glucuronosyltransferase (UGT) enzymes is expected to become a more prominent pathway in the metabolism of new drug candidates designed by pharmaceutical companies. Therefore, determining the abundance and activity of these enzymes is of value in the process of scaling in vitro data to in vivo metabolic parameters. Many of the studies involving the measurement of UGTs were conducted with too few samples, which did not provide a good indication of population values and the level of variability. Meta-analysis is used in the current study to combine all reported values (eight studies that used LC-MS isotope-labelled standard targeted quantitative methods), detect inconsistencies between the various datasets and describe correlations of expression between the quantified UGT enzymes. Some heterogeneity was observed between studies, especially in the UGT1A4, 2B7 and 2B10 datasets. However, in the absence of information on the inter-laboratory consistency of assays, it is difficult to assign these differences to the heterogeneity of the samples. Large inter-individual variability was observed in the collated data across this family of enzymes. Positive correlations between the expression levels of certain UGT enzymes were found in the collated data. These included the pairs: UGT1A4/2B4 (rs=0.71, p<0.0001, n=82), UGT2B4/2B15 (rs=0.63, p<0.0001, n=83), UGT2B7/2B15 (rs=0.81, p<0.0001, n=99). These correlations can be explained by common regulatory mechanisms involved in the expression of these proteins.