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PHARMACOGENETIQUE DES MEDICAMENTS THIOPURINIQUES Implication des enzymes TPMT et IMPDH2 et de la RhoGTPase RAC1

Abstract : The thiopurine drugs, azathioprine, 6-mercaptopurine and 6-thioguanine, have been used for decades for their cytotoxic and immunosuppressive properties in the treatment of leukemias, chronic inflammatory or autoimmune diseases and in the prevention of allograft rejection. However, some patients treated with conventional doses of these molecules develop very severe side effects. The deficient activity of the thiopurine S-methyltransferase (TPMT), an enzyme involved in thiopurine inactivation, is one of the key factors in the myelotoxicity of these drugs. The determination of the TPMT phenotype by genotyping test is a preventive measure before the initiation of thiopurine therapy and is based on the identification of the most common inactivating mutations of the TPMT gene. First, our study consisted in the functional analysis of four new allelic variants of TPMT, using an heterologous expression system, the yeast S. cerevisiae. The non-functional character of two of those variants was demonstrated. However, TPMT deficiency explain only about 30 % of cases of thiopurine myelotoxicity, suggesting the existence of other genetic abnormalities affecting other genes involved in the response toward thiopurines. Accordingly, we studied the genetic polymorphism of two other proteins, the inosine monophosphate dehydrogenase type 2 (IMPDH2), a key enzyme in the production of the active metabolites of thiopurine, and the RhoGTPase RAC1, which is one of the pharmacological targets of these molecules. Some of the polymorphisms that we identified in those two genes seem to affect in vitro the expression and / or activity of these proteins and, therefore, could contribute to inter-individual variations of the response to thiopurine
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https://tel.archives-ouvertes.fr/tel-00439266
Contributor : Anne Garat <>
Submitted on : Monday, December 7, 2009 - 10:58:32 AM
Last modification on : Friday, October 23, 2020 - 4:33:47 PM
Long-term archiving on: : Thursday, June 17, 2010 - 11:22:04 PM

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  • HAL Id : tel-00439266, version 1

Citation

Anne Garat. PHARMACOGENETIQUE DES MEDICAMENTS THIOPURINIQUES Implication des enzymes TPMT et IMPDH2 et de la RhoGTPase RAC1. Biochimie [q-bio.BM]. Université du Droit et de la Santé - Lille II, 2009. Français. ⟨tel-00439266⟩

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