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ToxSci Advance Access originally published online on February 3, 2009
Toxicological Sciences 2009 108(2):419-426; doi:10.1093/toxsci/kfp022
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Inhibiting the Teratogenicity of the Immunosuppressant Leflunomide in Mice by Supplementation of Exogenous Uridine

Ryou Fukushima*,1, Susumu Kanamori*, Masahiro Hirashiba*, Atsuko Hishikawa*, Ri-ichi Muranaka*, Masako Kaneto* and Hiroshi Kitagawa{dagger}

* Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan {dagger} Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1, Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan

1 To whom correspondence should be addressed. Fax: +81-6-6332-6385. E-mail: ryou.fukushima{at}shionogi.co.jp.

Received November 19, 2008; accepted January 22, 2009


  Abstract

Leflunomide is an immunosuppressant drug displaying teratogenicity in mice, rats, and rabbits. Its immunosuppressive effect occurs via inhibition of dihydroorotate dehydrogenase (DHODH) and tyrosine kinases. In this study, we coadministered Leflunomide and uridine, a precursor substance of pyrimidine nucleotides, to pregnant CD-1 mice, and examined whether or not a decreased level of intracellular pyrimidine nucleotides with inhibition of DHODH is related to the teratogenicity of Leflunomide. Then we examined the alteration of the nucleotide level in fetal tissue by Leflunomide and the effect of coadministered uridine. We administered Leflunomide with or without uridine to pregnant mice on gestation day 10, and used the vehicle of Leflunomide as a control. Leflunomide caused multiple malformations in all fetuses, but coadministration with uridine inhibited most of its teratogenicity. Leflunomide decreased the concentration of pyrimidine nucleotides, not purine nucleotides, whereas uridine coadministered with Leflunomide partially restored the level of pyrimidine nucleotides. These results indicate that the inhibitory effect of DHODH activity is related to the teratogenicity of Leflunomide.

Key Words: dihydroorotate dehydrogenase; Leflunomide; mice; pyrimidine nucleotide; teratogenicity.


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