title: Interaction between oblongifolin C and UDP-glucuronosyltransferase isoforms in human liver and intestine microsomes.
abstract: 1. Oblongifolin C (OC) is a potential natural anticancer candidate, and its metabolic profile has not yet been established. 2. One major OC glucuronidation metabolite (OCG) has been identified in a pool of human liver microsomes (HLMs). Chemical inhibition experiments suggested that OCG was mainly formed by UGT1A. A screen of recombinant UDP-glucuronosyltransferase isoforms (UGTs) indicated that UGT1A1 primarily mediates OC conjugation, with minor contributions from UGT1A3 and UGT1A8. Enzyme kinetic studies showed that UGT1A1 was the main UGT isoform involved in OCG in HLMs. 3. Further investigation suggested that OC is a broad inhibitor of UGTs. Additionally, OC competitively inhibited UGT1A6 with a Ki value of 3.49 ± 0.57 μM, whereas non-competitively inhibited UGT1A10 with a Ki value of 2.12 ± 0.18 μM. 4. Understanding the interaction between OC and UGTs will greatly contribute to future investigations regarding the inter-individual differences in OC metabolism in clinical trials and potential drug-drug interactions.
authors.affiliation: Department of Pharmacology, Shanghai University of Traditional Chinese Medicine , Shanghai , China and.
authors.forename: Cui
authors.initials: C
authors.lastname: Gao
authors.forename: Rong
authors.initials: R
authors.lastname: Shi
authors.forename: Tianming
authors.initials: T
authors.lastname: Wang
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Tan
authors.forename: Hongxi
authors.initials: H
authors.lastname: Xu
authors.forename: Yueming
authors.initials: Y
authors.lastname: Ma
mesh_terms: D002853:Chromatography, Liquid; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011994:Recombinant Proteins / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020719:Glucuronides; D007527:Isoenzymes; D011994:Recombinant Proteins; D012838:Silymarin; D013729:Terpenes; C575447:oblongifolin C; D000077385:Silybin; D014453:Glucuronosyltransferase
keywords: Drug–drug interactions; UGT1A1; glucuronidation; human intestine microsomes; human liver microsomes