title: Enantiomeric activation of glucuronidation in dog hepatic microsomes.
abstract: Isomer-specific mechanisms of conjugation were investigated by evaluating the hepatic glucuronidation of the enantiomers of the 5-lipoxygenase inhibitor zileuton. The glucuronidation of the individual isomers was stereoselective, as dog hepatic microsomes glucuronidated the S-isomer but failed to generate a glucuronide conjugate of the R-isomer. In combination, the nonglucuronidated R-isomer caused a concentration-dependent increase in the rate of glucuronidation of its enantiomorph. Kinetic analysis of this interaction indicated that the R-isomer affected rates of glucuronidation by decreasing the Km of the S-isomer for this process. This effect appeared enantioselective as the achiral analogue A-65838 had no effect on the Vmax and Km of S-isomer glucuronidation. The data were modeled using Michaelis-Menten kinetics in which the Km of S-isomer glucuronidation was reduced in a saturable manner by the concentration of the R-isomer. These data indicate that the nonconjugated R-isomer competitively activates the glucuronidation of its enantiomorph. To our knowledge, these data represent the first demonstration of enantiomeric activation of an enzyme involved in hepatic drug metabolism.
authors.affiliation: Department of General Pharmacology, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: D J
authors.initials: DJ
authors.lastname: Sweeny
authors.forename: H N
authors.initials: HN
authors.lastname: Nellans
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005965:Glucuronates / Q000378:metabolism*; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D005965:Glucuronates; D016859:Lipoxygenase Inhibitors; C063449:zileuton; D006918:Hydroxyurea