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The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction.

Authors: Weglicki, WB  Kramer, JH  Spurney, CF  Chmielinska, JJ  Mak, IT 
Citation: Weglicki WB, etal., Can J Physiol Pharmacol. 2012 Aug;90(8):1145-9. doi: 10.1139/y2012-023. Epub 2012 May 30.
Pubmed: (View Article at PubMed) PMID:22646904
DOI: Full-text: DOI:10.1139/y2012-023

We determined whether the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine (tyrphostin AG-1478) causes hypomagnesemia and cardiac dysfunction in rats. Tyrphostin was administered (3 times per week, intraperitoneal injection, to achieve 21.4 mg.(kg body mass)(-1).day(-1)) to normomagnesemic rats for 5 weeks. Levels of magnesium in the plasma of the tyrphostin-treated rats decreased significantly by the following amount: 17% at week 1, 27% at week 2, and 26%-35% between weeks 3 to 5. Levels of the plasma lipid peroxidation marker 8-isoprostane rose significantly: by 58% at week 1, 168% at week 3, and 113% at week 5. At week 5, blood neutrophils from the tyrphostin-treated group displayed a 2.26-fold higher basal level of O(2)(.-) generation; the ratio of oxidized glutathione (glutathione disulfide; GSSG) to reduced glutathione (GSH) in the red blood cells increased 2.5-fold. At week 5, echocardiography revealed that TKI treatment resulted in significant cardiac systolic dysfunction, with impaired diastolic function and dilated cardiomyopathy. Since hypomagnesemia alone can trigger oxidative stress and cardiac injury, we suggest that inhibition of EGFR-TK caused magnesium wasting, which partly contributed to decreased cardiac contractility.

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CRRD Object Information
CRRD ID: 7204501
Created: 2012-12-21
Species: All species
Last Modified: 2012-12-21
Status: ACTIVE



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