UGT2B1 Inhibitors

Chemical inhibitors of UGT2B1 employ various mechanisms to hinder the enzyme's function. Probenecid, for instance, competes with the natural substrates of UGT2B1 due to its structural resemblance to uric acid, effectively blocking the enzyme's active site and preventing substrate binding. Similarly, Niflumic acid and Gemfibrozil both inhibit UGT2B1 by direct competition at the active site, which obstructs the glucuronidation process that UGT2B1 facilitates for other substrates. Valproic acid uniquely acts as both a substrate and an inhibitor; it can saturate UGT2B1, leading to substrate inhibition where the enzyme's activity is limited due to the high concentration of the inhibitor itself. Atazanavir reduces the enzyme's activity by occupying the active site, which diminishes the glucuronidation rate of drugs metabolized by UGT2B1. Fluconazole and Ketoconazole inhibit UGT2B1 through direct binding, which may alter the enzyme's conformation or block substrate access, respectively.

Further, Sorafenib and Indomethacin inhibit UGT2B1 through competitive inhibition, where they bind to the enzyme's active site in place of the natural substrates, thus preventing the usual metabolic processes. Chrysin forms a complex with UGT2B1, which disrupts the normal interaction between the enzyme and its substrates, leading to a decrease in glucuronidation activity. Isoniazid directly interacts with the active site of UGT2B1, which results in diminished glucuronidation capacity of the enzyme. Finally, Mefenamic acid serves as a competitive inhibitor by occupying the substrate binding region of UGT2B1, which blocks the substrates from accessing the site necessary for their metabolism and thereby inhibits the enzyme's function. Each of these chemicals targets the enzymatic activity of UGT2B1, resulting in a reduction of the enzyme's ability to process its substrates through the glucuronidation pathway.