Enantiomeric activation of glucuronidation in dog hepatic microsomes

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.