The effect of obesity on UGT enzyme expression, activity and modeled hepatic clearance by glucuronidation

Abstract

The uridine 5'-diphospho-glucuronosyltransferases (UGTs) are, arguably, the most important pathway of conjugative metabolism. Despite this, little is known about how they may be impacted by demographic variables such as obesity or sex. Since obesity is 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 these changes might also impair UGT enzymes. Using biochemical activity assays, mass spectrometry and protein immunoblot, we show that with increasing obesity there is reduced activity 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. When physiologically-based pharmacokinetic modeling was used, the total liver clearance for the substrates used was significantly lower for UGT1A, 1A9, and 1A4/trifluoperazine (an a-typical antipsychotic drug). Categorized clearance was significantly lower in the obese group for isoforms 1A6 and 2B7. Sex differences exist that are isoform specific. Activities of UGT1A1, 1A6 and 1A9 were significantly decreased with increasing BMI in males, but not females, which showed general 1A to be significantly decreased in the obese group. Finally, an unintended but beneficial outcome from this study was to demonstrate excellent concordance between mass spectrometry and protein levels for UGT1A1, 1A6, 1A9 and 2B7 in these adult samples. In addition, mass spectrometry shows very good concordance with fluorescence activity for UGT1A1 and 1A9 in adults, demonstrating the utility of fluorescence-based approaches. In summary, the activities of UGT enzymes are decreased by obesity and there may be sex differences within this result.