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Molecular and Cellular Biology, July 2002, p. 5212-5221, Vol. 22, No. 14
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.14.5212-5221.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of Both Thymidine Phosphorylase and Uridine Phosphorylase and Consequent Disorders in Mice

Department of Cancer Chemotherapy, Institute for Cancer Research,,¹ Third Department of Internal Medicine,³ Department of Pathology, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520,¹⁰ Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno, Saitama,,² Department of Biophysics, Graduate School of Pharmaceutical Sciences,,⁴ Department of Immunology, Medical Institute of Bioregulation,⁸ Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582,⁹ Department of Pathology, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550,⁵ Institute for Medical Science of Aging, Aichi Medical University, Aichi-gun, Aichi 480-1195,⁶ First Department of Pathology, Gunnma University School of Medicine, Maebashi 371-8511,⁷ Department of Biochemistry,¹¹ Department of Cell Biology, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo 170-8455,¹⁵ Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama,,¹² Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305,¹³ Department of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto, Japan,¹⁴

Received 11 March 2002/ Accepted 26 March 2002

Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP^-/- UP^-/-) mice. TP activities were inhibited in TP^-/- UP^-/- mice, and the level of thymidine in the plasma of TP^-/- UP^-/- mice was higher than for TP^-/- mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP^-/- UP^-/- mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T₂ maps in the brain and axonal edema by electron microscopic study of the brain in TP^-/- UP^-/- mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.

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