The effects of genetics, epigenetics and obesity on ugt enzyme expression, activity and modeled hepatic clearance

Abstract

The uridine 5'-diphospho-glucuronosyltransferases (UGTs) are, arguably, the most important pathway of conjugative metabolism responsible for inactivation of such chemicals as exogenous chemicals as propofol and endogenous compounds like testosterone and bilirubin. Despite this, little is known about how they may be impacted by demographic variables such as ethnicity, obesity or sex. With obesity at epidemic proportions worldwide, this has important implications for drug and chemical toxicity. We hypothesized that since obesity causes a number of changes to both the phenotype and function of the liver, that UGT impairment might occur. Using biochemical activity assays, mass spectrometry and protein immunoblot, we show that with increasing obesity activity is reduced for isoforms UGT1A, 1A4, and 1A9. When all obese individuals are classified as "overweight and/or obese" and compared to normal weight individuals (utilizing body mass index categories established by the Centers for Disease Control), we see that isoforms 1A1, 1A6, 1A9 and 2B7 have significantly lower activity for the overweight group. Physiologically-based pharmacokinetic modeling was also used to show the total liver clearance for the substrates used was significantly lower for UGT1A, 1A9, and 1A4 and lower for 1A6 and 2B7 when catgorized. Isoform specific sex differences exist showing activities of UGT1A1, 1A6 and 1A9 significantly decreased with increasing BMI in males, but not females, which showed general 1A to be significantly decreased in the obese group. Comparisons illustrated excellent concordance between mass spectrometry and protein levels for UGT1A1, 1A6, 1A9 and 2B7 and with fluorescence activity for UGT1A1 and 1A9. In short, the activities of UGT enzymes are decreased by obesity and there may be sex differences within this result. Though not able to elucidate the cause of the impairment to UGT activity and clearance, ethnically linked epigenetic regulation of UGT2B15 gene expression was seen that is tethered to a deletion of the UGT2B17 both of which have important implications in androgen metabolism.