title: Regioselective glucuronidation of gingerols by human liver microsomes and expressed UDP-glucuronosyltransferase enzymes: reaction kinetics and activity correlation analyses for UGT1A9 and UGT2B7.
abstract: OBJECTIVE
  To determine the reaction kinetics for regioselective glucuronidation of gingerols (i.e. 6-, 8- and 10-gingerol) by human liver microsomes and expressed UDP-glucuronosyltransferase (UGT) enzymes, and to identify the main UGT enzymes involved in regioselective glucuronidation of gingerols.
  
  
  METHODS
  The rates of glucuronidation were determined by incubating the gingerols with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Activity correlation analyses were performed to identify the main UGT enzymes contributing to hepatic metabolism of gingerols.
  
  
  RESULTS
  Glucuronidation at the 4'-OH group was much more favoured than that at 5-OH. The degree of position preference was compound-dependent; the catalytic efficiency ratios of 4'-O- to 5-O-glucuronidation were 9.1, 19.7 and 2.9 for 6-, 8- and 10-gingerol, respectively. UGT1A8 (an intestinal enzyme), UGT1A9 and UGT2B7 were the enzymes showing the highest activity towards gingerols. Formation of 5-O-glucuronide was mainly catalysed by UGT1A9. UGT2B7 was the only enzyme that generated glucuronides at both 4'-OH and 5-OH sites, although a strong position preference was observed with 4'-OH (≥80.2%). Further, activity correlation analyses indicated that UGT2B7 and UGT1A9 were primarily responsible for 4'-O-glucuronidation and 5-O-glucuronidation of gingerols in the liver, respectively.
  
  
  CONCLUSIONS
  Gingerols were metabolized by multiple hepatic and gastrointestinal UGT enzymes. Also, UGT1A9 and 2B7 were the main contributors to regioselective glucuronidation of gingerols in the liver.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Zhufeng
authors.initials: Z
authors.lastname: Wu
authors.forename: Hongming
authors.initials: H
authors.lastname: Liu
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D002396:Catechols / Q000378:metabolism / Q000493:pharmacokinetics*; D005233:Fatty Alcohols / Q000378:metabolism / Q000493:pharmacokinetics*; D020939:Zingiber officinale / Q000737:chemistry*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver; D010936:Plant Extracts / Q000378:metabolism / Q000493:pharmacokinetics*; D000090264:UDP-Glucuronosyltransferase 1A9; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
chemical_list: D002396:Catechols; D005233:Fatty Alcohols; D020719:Glucuronides; D010936:Plant Extracts; C000715591:UGT1A9 protein, human; D014535:Uridine Diphosphate Glucuronic Acid; C007845:gingerol; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9
keywords: UDP-glucuronosyltransferases; ginger; gingerols; glucuronidation; substrate inhibition