title: Investigation of UDP-glucuronosyltransferases (UGTs) inhibitory properties of carvacrol.
abstract: UDP-glucuronosyltransferases (UGTs), the most important phase II drug metabolizing enzymes (DMEs), could metabolize many drugs and various endogenous substances including bilirubin, steroid hormones, thyroid hormones, bile acids and fat-soluble vitamins. Evaluation of the inhibitory effects of compounds on UGTs is clinically important because inhibition of UGT isoforms could not only result in serious drug-drug interactions (DDIs), but also induce metabolic disorders of endogenous substances. The aim of the present study was to investigate the inhibitory effects of carvacrol on major UGT isoforms. The results showed that carvacrol could inhibit the activity of UGT1A9 with negligible effects on other UGT isoforms. When 4-methylumbelliferone (4-MU) was used as a nonspecific probe substrate and recombinant UGT enzymes were utilized as an enzyme resource, the inhibition of UGT1A9 was best fit to the competitive type and the inhibition kinetic parameter (K(i)) was calculated to be 5.7 µM. Furthermore, another specific probe substrate, propofol, was employed to determine the inhibitory kinetics of UGT1A9, and the results demonstrated that the inhibitory type was noncompetitive. The inhibition kinetic parameter (K(i)) was determined to be 25.0 µM. Because this substrate-dependent inhibition of UGT1A9 might confuse the in vitro-in vivo extrapolation, these in vitro inhibition kinetic parameters should be interpreted with special caution.
authors.affiliation: Department of Clinical Pharmacology, Affiliated Hospital, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Dong
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Zhu
authors.forename: Si-Cheng
authors.initials: SC
authors.lastname: Liang
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Ze-Yuan
authors.initials: ZY
authors.lastname: Liu
mesh_terms: D000081007:Cymenes; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D041743:Herb-Drug Interactions; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000378:metabolism; D007527:Isoenzymes; D007700:Kinetics; D039821:Monoterpenes / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D011994:Recombinant Proteins
chemical_list: D000081007:Cymenes; D007527:Isoenzymes; D039821:Monoterpenes; D010936:Plant Extracts; D011994:Recombinant Proteins; D006923:Hymecromone; C073316:carvacrol; D014453:Glucuronosyltransferase