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Species-specificity of pyrimethamine in the rodent bone marrow micronucleus test
1National Veterinary Assay Laboratory, Tokyo, Japan.
Abstract:
An antiprotozoal agent pyrimethamine is a potent clastogen that induces structural chromosome aberrations and micronuclei in cultured Chinese hamster (CHL) cells in vitro. Our previous study on the compound, however, demonstrated no significant induction of micronuclei in the mouse bone marrow micronucleus test, even with dosings on 4 consecutive days. In the present study, we investigated the clastogenicity of pyrimethamine in the rat bone marrow micronucleus test. An obvious dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes (MNPCEs) was observed when the compound was given 3 times by oral gavage at 20-120 mg/kg/day. The MNPCE frequency at the highest dose was 80 times that of the control group. Single dose of pyrimethamine at 80 and 160 mg/kg also significantly induced MNPCEs. Thus, pyrimethamine showed species-specific effects in rodent bone marrow micronucleus assays. Our finding implies that micronucleus tests using not only mouse, but also rat, may be necessary for the evaluation of clastogens detected in in vitro cytogenetic studies.
Insights
Pyrimethamine, an antiprotozoal drug, is a clastogen in vitro but showed species-specific effects in vivo. Rat bone marrow micronucleus tests revealed significant induction of micronucleated polychromatic erythrocytes (MNPCEs), unlike in mice.
Area of Science:
- Genotoxicity testing
- In vivo cytogenetics
- Drug safety evaluation
Background:
- Pyrimethamine is an antiprotozoal agent with known in vitro clastogenic activity.
- Previous mouse studies showed no significant induction of micronuclei.
- In vitro cytogenetic studies indicated pyrimethamine induces chromosome aberrations.
Purpose of the Study:
- To investigate the clastogenicity of pyrimethamine in the rat bone marrow micronucleus test.
- To compare the in vivo genotoxic effects of pyrimethamine between mice and rats.
- To evaluate the necessity of rat micronucleus tests for clastogen assessment.
Main Methods:
- Administration of pyrimethamine via oral gavage to rats.
- Dosing regimens included multiple doses (20-120 mg/kg/day) and single doses (80 and 160 mg/kg).
- Analysis of micronucleated polychromatic erythrocytes (MNPCEs) in rat bone marrow.
Main Results:
- A significant, dose-dependent increase in MNPCE frequency was observed in rats.
- The highest dose resulted in an 80-fold increase in MNPCEs compared to controls.
- Single doses of pyrimethamine also significantly induced MNPCEs in rats.
Conclusions:
- Pyrimethamine exhibits species-specific genotoxic effects in rodent bone marrow micronucleus assays.
- Rat bone marrow micronucleus tests are crucial for evaluating clastogens identified in vitro.
- Combined mouse and rat micronucleus testing may be necessary for comprehensive genotoxicity assessment.