Mechanism of induction of micronuclei and chromosome aberrations in mouse bone marrow by multiple treatments of methotrexate
| Autor: | Daishiro Miura, Kimie Yagi, Yasuharu Nakai, Keiko Hirabayashi, Tokutaro Makita, Yoshinori Kasahara |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Male
medicine.drug_class Ratón Bone Marrow Cells Toxicology Antimetabolite Mice chemistry.chemical_compound Bone Marrow Dihydrofolate reductase Genetics medicine Animals Chromatography High Pressure Liquid Chromosome Aberrations Micronucleus Tests biology Molecular biology Kinetics Tetrahydrofolate Dehydrogenase Methotrexate medicine.anatomical_structure chemistry Sephadex Micronucleus test Antifolate Immunology biology.protein Folic Acid Antagonists Bone marrow Mutagens medicine.drug |
| Zdroj: | Mutation Research/Genetic Toxicology. 280:117-128 |
| ISSN: | 0165-1218 |
| DOI: | 10.1016/0165-1218(92)90007-m |
| Popis: | Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR), slightly induced micronuclei and this induction of micronuclei was enhanced by multiple treatments with the drug (Yamamoto et al., 1981; Hayashi et al., 1984; CSGMT/JEMS · MMS, 1990). More micronuclei and chromosomal aberrations in mouse bone marrow cells were induced by multiple than by single treatment. The MTX level in mouse plasma and bone marrow showed little (or no) differences between single and quadruple treatments several hours after the injection(s). On the other hand, the DHFR activity in bone marrow cells 3 h after one and four injections was decreased to approximately 38 and 0%, respectively, of that in non-treated mice. Furthermore, the intracellular MTX level in the bone marrow cells (but not in total bone marrow) after four injections was about 10-fold higher than that after one injection. The amount of MTX bound to protein 3 h after four injections, as assayed by gel filtration (Sephadex G-25), was approximately 8-fold greater than after one injection. Therefore, the multiple-dose effects of MTX on the induction of micronuclei and chromosomal aberrations may be explained by the intracellular accumulation of MTX resulting in an enhancement of enzyme inhibition. |
| Databáze: | OpenAIRE |
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