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Enantioselective induction of peroxisomal proliferation in CD-1 mice by leukotriene antagonists
S J Grossman1, J G DeLuca, R J Zamboni
1Department of Safety Assessment, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
Abstract:
The effects of a racemic leukotriene antagonist (MK-0571) and its component enantiomers (L-668,018 and L-668,019) on hepatic peroxisome proliferation were examined in mice, rats, and rhesus monkeys. Administration of racemic MK-0571 to mice resulted in increased liver weights, increased peroxisomal volume density, and a pleiotropic induction of characteristic peroxisomal and nonperoxisomal enzyme activities associated with peroxisomal proliferation. When the individual enantiomers of MK-0571 were administered to mice, a pronounced enantioselective induction of peroxisome proliferation was observed. Toxicokinetic studies showed that the levels of each enantiomer in the liver or plasma after separate administration were similar. Thus, the enantioselectivity in the induction of peroxisome proliferation could not be explained on the basis of pharmacokinetic differences between the enantiomers. The hepatic peroxisomal response of the rat to MK-0571 was greatly attenuated compared to the mouse. As has been seen with other peroxisome-proliferating agents, MK-0571 had no effect on either peroxisomal volume density or peroxisomal enzyme activity in monkeys. Due to the high degree of enantiomeric discrimination toward the induction of peroxisomal proliferation by these enantiomers, compounds of this type may prove useful as probes to examine the mechanisms by which peroxisomal proliferating agents induce their effects.
Insights
The leukotriene antagonist MK-0571 enantiomers selectively induced hepatic peroxisome proliferation in mice, but not rats or monkeys. This enantioselectivity, independent of pharmacokinetics, suggests potential as probes for proliferation mechanisms.
Area of Science:
- Hepatology
- Toxicology
- Pharmacology
Background:
- Hepatic peroxisome proliferation is a biological response to certain xenobiotics.
- Leukotriene antagonists are a class of drugs with potential effects on liver function.
Purpose of the Study:
- To investigate the effects of racemic MK-0571 and its enantiomers on hepatic peroxisome proliferation in different species.
- To determine if observed effects are enantioselective and explore underlying mechanisms.
Main Methods:
- Administration of racemic MK-0571 and its enantiomers (L-668,018, L-668,019) to mice, rats, and rhesus monkeys.
- Assessment of liver weights, peroxisomal volume density, and enzyme activities.
- Toxicokinetic studies to analyze enantiomer levels in plasma and liver.
Main Results:
- Racemic MK-0571 induced significant peroxisome proliferation in mice, characterized by increased liver weight and enzyme activity.
- A pronounced enantioselective induction of peroxisome proliferation was observed in mice, with similar enantiomer pharmacokinetics.
- The response was attenuated in rats and absent in rhesus monkeys, indicating species-specific effects.
Conclusions:
- MK-0571 enantiomers exhibit significant enantioselectivity in inducing hepatic peroxisome proliferation in mice.
- Pharmacokinetic differences do not explain the observed enantioselectivity.
- These enantiomers may serve as valuable tools for studying the mechanisms of peroxisome proliferator-induced effects.
