Inhibitory effect of hesperetin and naringenin on human UDP-glucuronosyltransferase enzymes: Implications for herb-drug interactions

Abstract

Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) and Aurantii Fructus Immaturus. The present study aims to investigate the inhibition potential of HET and NGR derivatives towards one of the most important phase II drug-metabolizing enzymes-uridine diphosphate (UDP)-glucuronosyltransferases (UGTs). We used trifluoperazine as a probe substrate to test UGT1A4 activity, and recombinant UGT-catalyzed 4-methylumbelliferone glucuronidation was used as a probe reaction for other UGT isoforms. Data show that HET and NGR displayed broad-spectrum inhibition against human UGTs. Besides, HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC50 and Ki values lower than 10 μM), and the inhibitory effects of NGR against three major UGTs, including UGT1A1, 1A3 and 2B7. In a combination of inhibition parameters (Ki) and in vivo concentration of HET and NGR, the potential in vivo inhibition magnitude was predicted. Based on the reported maximum plasma concentration of HET and NGR in vivo, these findings indicate the potential herb-drug interactions (HDI) between HET or NGR and the drugs mainly undergoing UGT1A3 or UGT2B7 catalyzed metabolic elimination. Considering the variety of citrus that contains HET and NGR, so caution should be applied when taking drugs that utilize UGTs for metabolism and clearance with citrus fruits.