{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nStudies have demonstrated that UGT2B10 plays a central role in nicotine metabolism by catalyzing the N‐glucuronidation reaction. In particular, UGT2B10 directly conjugates nicotine with glucuronic acid at its aromatic nitrogen atom, thereby promoting its inactivation. This enzyme, which had been previously unrecognized for activity toward nicotine, has now been shown to mediate a major metabolic pathway that detoxifies nicotine and its oxidative metabolite, cotinine."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nKinetic studies in recombinant systems and human liver microsomes have further clarified that UGT2B10 exhibits high affinity for nicotine and cotinine—with Michaelis-Menten constants comparable to those measured in vivo—and outperforms other UGT isoforms such as UGT1A4 in this specific reaction. Moreover, investigations of substrate specificity revealed that UGT2B10 preferentially conjugates certain tertiary amine structures, establishing it as the principal hepatic enzyme responsible for nicotine N-glucuronidation. Genetic polymorphisms within the UGT2B10 gene, including missense and splice variants, have been associated with markedly reduced glucuronidation activity in vitro, underscoring the enzyme’s clinical relevance in determining individual nicotine clearance rates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPopulation-based analyses further indicate that variability in UGT2B10 genotype significantly influences the relative contributions of nicotine metabolic pathways. In ethnically diverse cohorts, subjects carrying reduced-function UGT2B10 alleles exhibit lower urinary levels of nicotine and cotinine glucuronides and compensatory increases in alternative metabolic routes, such as cytochrome P450 2A6-mediated oxidation. This genetic effect on nicotine metabolism likely contributes to inter-individual and inter-ethnic differences in smoking behavior and lung cancer risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sanna Kaivosaari, Päivi Toivonen, Leah M Hesse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicotine glucuronidation and the human UDP-glucuronosyltransferase UGT2B10."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.107.037093"}], "href": "https://doi.org/10.1124/mol.107.037093"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17576790"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17576790"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Gang Chen, Andrea S Blevins-Primeau, Ryan W Dellinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr) polymorphism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-2245"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-2245"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17909004"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17909004"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gang Chen, Nino E Giambrone, Douglas F Dluzen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glucuronidation genotypes and nicotine metabolic phenotypes: importance of functional UGT2B10 and UGT2B17 polymorphisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-4582"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-4582"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20876810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20876810"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yukiko Kato, Takeshi Izukawa, Shingo Oda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human UDP-glucuronosyltransferase (UGT) 2B10 in drug N-glucuronidation: substrate screening and comparison with UGT1A3 and UGT1A4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Drug Metab Dispos (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/dmd.113.051565"}], "href": "https://doi.org/10.1124/dmd.113.051565"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23611809"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23611809"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sharon E Murphy, Sung-Shim L Park, Elizabeth F Thompson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgu191"}], "href": "https://doi.org/10.1093/carcin/bgu191"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25233931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25233931"}]}]}]}