{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUGT2B4 is a major UDP‐glucuronosyltransferase that plays a pivotal role in hepatic detoxification, primarily by converting hydrophobic bile acids into more hydrophilic glucuronide derivatives. Its expression is directly regulated by nuclear receptors—most notably, the bile acid sensor FXR and the peroxisome proliferator‐activated receptor alpha (PPARα)—thereby linking bile acid synthesis, transport, and detoxification with lipid and cholesterol metabolism. These regulatory mechanisms ensure that potentially cytotoxic bile acids are efficiently rendered less toxic and more readily excretable"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "<br><br>\nBeyond its role in bile acid detoxification, UGT2B4 exhibits overlapping substrate specificity with other UGT members, notably UGT2B7, enabling it to conjugate a variety of endogenous compounds such as steroid hormones and catechol estrogens, as well as xenobiotics including drugs like carvedilol, codeine, and clopidogrel. Structure–function studies have identified key amino acid residues (e.g., at position 33) that are critical for enzymatic activity and substrate selectivity, while genetic polymorphisms (such as Asp458Glu and novel nonsynonymous variants) further influence its catalytic efficiency. These variations have important implications not only for drug metabolism and pharmacokinetics but also for the clearance of toxic metabolites, as seen in experimental systems assessing UGT2B4’s contribution to 6-glucuronidation reactions"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "8"}]}, {"type": "t", "text": "<br><br>\nClinically, UGT2B4’s expression and functional variability have been implicated in diverse disease susceptibilities and physiological processes. Variations in its regulatory regions and coding sequence have been associated with differential clearance of steroid hormones, influencing traits such as age at menarche and susceptibility to hormone‐related cancers (e.g., breast and esophageal cancers), as well as impacting the risk of drug‐induced liver injury and other detoxification‐related pathologies. In addition, compensatory increases in UGT2B4 expression have been observed to counterbalance deficiencies in alternative bile acid–conjugating enzymes under cholestatic conditions. Together with studies outlining interindividual differences and evolutionary signatures of balancing selection in its upstream regulatory regions, these findings underscore the central role of UGT2B4 in maintaining homeostasis of both endogenous and xenobiotic compounds."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Olivier Barbier, Ines Pineda Torra, Audrey Sirvent, et al. 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