Inhibitory Effects of Endogenous Linoleic Acid and Glutaric Acid on the Renal Glucuronidation of Berberrubine in Mice and on Recombinant Human UGT1A7, 1A8, and 1A9

Abstract

Berberrubine (BRB) has a strong lipid-lowering effect and can be extensively metabolized into berberrubine-9---d-glucuronide (BRBG) in vivo. Recently, pharmacokinetics studies showed that the production of BRBG was significantly decreased in the urine of mice fed with a high-fat diet (HFD), indicating a decreased glucuronidation capacity. Based on the UDP-glucuronosyltransferase (UGT) isoform identification, hepatic and renal microsomal incubation, glucuronidation was examined to suggest the metabolism of BRB in liver and kidneys. The results showed that the renal UGT activity for metabolizing BRB markedly decreased, which may be highly related to the decreased expression and activity of renal Ugt1a7c. Surprisingly, in vitro studies revealed neither BRB nor BRBG inhibited the renal UGT activity. By employing an integrated strategy of metabolomics and pharmacokinetics, we identified and confirmed for the first time the inhibitory effect of some potential endogenous molecules on the renal glucuronidation of C57BL/6J mice, such as glutaric acid (GA) and linoleic acid (LA). By employing recombinant human UGTs, we found that GA and LA efficiently affect the activity of recombinant human UGT1A7, 1A9, and 1A8 at their normal or abnormal physiologic levels in vivo. GA (2 mM) markedly inhibited the activity of UGT1A7 by 89.4% and UGT1A9 by 32.8%. The inhibition rates reached 99.3% for UGT1A9, 48.3% for UGT1A7, and 46.8% for UGT1A8 with LA at 200 M. It has been suggested that the endogenous molecules have the potential to affect the efficiency of glucuronidation, which might be a key factor contributing to individual differences in drug metabolism.

High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice

“…Ugt1a9 encodes an enzyme responsible for hydroxyl and phenol glucuronidation. Substrates of UGT1A9 involve lots of nature products such as flavonoids, tanshinone, and some alkaloids [16][17][18][19], as well as important synthetic drugs such as propofol [20], 4methylumbelliferone [21], mycophenolic acid [22], and morphine [23]. In addition, UGT1A9 also participated in metabolism processes of endogenous signaling molecules like estradiol [24].…”

LC-QToF-Based Metabolomics Identifies Aberrant Tissue Metabolites Associated with a Higher-Fat Diet and Their ‘Reversion to Healthy’ with Dietary Probiotic Supplementation

“…Catalyzed by a family of uridine diphosphoglucuronate glucuronosyltransferases (UGT), glucuronidation is required for the detoxification of a variety of endogenous and exogenous metabolites [ 70 , 71 ]. Previous studies have correlated a higher-fat diet with reduced UGT transcription, and demonstrated that free fatty acids can act as inhibitors to various isoforms in the UGT family [ 72 , 73 , 74 ]. While these findings provide evidence that a higher-fat diet may lead to a suppression in glucuronidation and, subsequently, detoxification, further research is required to determine if the UDP-GlcA accumulation observed in our study is a direct result of UGT inhibition and/or repression.…”