Characterizations of Human UDP-Glucuronosyltransferase Enzymes in the Conjugation of p-Cresol

• DOI: 10.1093/toxsci/kfaa072
• Publication Date: 2020-05-13T11:55:18Z
• Authors: Yan Rong; Tony K L Kiang
• Keywords: Glucuronide

Abstract p-Cresol is a uremic toxin that formed by intestinal microbiota and extensively conjugated first-pass metabolism. glucuronide exerts various forms of cellular toxicity in vitro accumulated the plasma subjects with kidney disease, where associations adverse cardiovascular renal outcomes are evident. The objective this study was to determine contributions human UDP-glucuronosyltransferase (UGT) enzymes formation p-cresol glucuronide. Utilizing commonly expressed hepatic or recombinant UGTs (ie, hrUGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, 2B17), hrUGT1A6 hrUGT1A9 exhibited highest catalytic activities generation kinetics pooled liver microsomes were best described Hill equation substrate inhibition. Using inhibitory selective UGT inhibitors acetaminophen amentoflavone for UGT1A6 niflumic acid UGT1A9), identified predominant enzyme responsible production (78.4%–81.3% contribution) (54.3%–62.9%) microsomes, whereas UGT1A9 provided minor (2.8% 35.5%, respectively). relative (72.6 ± 11.3%, mean SD) (5.7 4.1%) individual from 12 adult donors highly variable, an inverse association (R = −.784, p .003) between contribution probe activity mycophenolic acid) Our novel findings provide valuable tools conducting further mechanistic studies designing clinical interventions mitigate toxicities associated