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Microarray analysis of Leflunomide-induced limb malformations in CD-1 mice.
Ryou Fukushima1, Masako Kaneto, Hiroshi Kitagawa
1Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & CO., Ltd., Osaka 561-0825, Japan. ryou.fukushima@shionogi.co.jp
Reproductive Toxicology (Elmsford, N.Y.)
|September 16, 2009
Summary
Leflunomide, an immunosuppressant, causes birth defects by inhibiting cell division in developing limbs. This teratogenic effect may stem from its impact on dihydroorotate dehydrogenase and tyrosine kinases.
Area of Science:
- Developmental toxicology
- Pharmacology
- Molecular biology
Background:
- Leflunomide is an immunosuppressant drug known to be teratogenic in animal models.
- It functions as a potent inhibitor of dihydroorotate dehydrogenase (DHODH) and tyrosine kinases.
Purpose of the Study:
- To investigate the molecular mechanisms underlying Leflunomide-induced teratogenicity.
- To explore the effects of Leflunomide on gene expression and cellular processes in embryonic limb development.
Main Methods:
- Pregnant mice were administered Leflunomide or a control vehicle on gestation day 10.
- Gene expression analysis was performed on embryonic limb buds at 4 and 24 hours post-treatment.
- Cellular mitosis in limb mesenchymal cells was assessed.
Main Results:
- Leflunomide treatment led to the down-regulation of cholesterol biosynthesis genes, but this did not correlate with teratogenicity.
- Leflunomide inhibited mitosis in limb mesenchymal cells.
- The observed effects suggest a link between DHODH inhibition, tyrosine kinase activity, and teratogenicity.
Conclusions:
- Leflunomide's teratogenicity in embryonic limb development is associated with the inhibition of cell mitosis.
- The mechanism may involve both DHODH inhibition and effects on tyrosine kinases crucial for signaling pathways.
