Synergistic and Additive Inhibition of UDP‐Glucuronosyltransferase 1A9 by Endogenous and Foodborne Inhibitors

ABSTRACT UDP‐glucuronosyltransferases (UGTs) are responsible for inactivation of a variety of drugs, endogenous hormones and environmental toxicants. Chemical inhibitors are a common factor decreasing UGT activities and furtherly inducing health problems. Although simultaneously encountering different inhibitors is readily to occur, no information is available for combined inhibition of UGT. This in vitro study investigates the combined inhibition of human UGT1A9 by endogenous and foodborne inhibitors (magnolol, di‐bromophenols, UDP). J values (the ratio of inhibitory rate to the remaining activity) are analysed to determine the combined inhibition type. The combined inhibition of di‐bromophenols and UDP obeys additive inhibition, in which combined J values equal to the sum of individual J values in alone inhibition assays. Meanwhile, there is a synergistic effect between 2,4‐di‐bromophenol and magnolol with combination index values ranging from 0.10 to 0.85. Further assays indicate that 2,4‐di‐bromophenol decreases IC 50 values for magnolol and vice versa. Kinetic analysis confirms that the two inhibitors and UGT1A9 can form a ternary complex with the inhibition constants of 0.0188 μM (magnolol) and 0.634 (2,4‐di‐bromophenol) μM. In summary, this study demonstrates that besides additive inhibition, synergistic inhibition is a probable occurrence in combined inhibition of UGT. It is suggested that the inhibitors can increase mutual inhibitory effects which deserves attentions in future UGT inhibition related studies.