RGD Reference Report - The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction. - Rat Genome Database

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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.
RGD ID: 7204501
Pubmed: PMID:22646904   (View Abstract at PubMed)
PMCID: PMC3734545   (View Article at PubMed Central)
DOI: DOI:10.1139/y2012-023   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dilated cardiomyopathy  ISOEgfr (Rattus norvegicus)7204501; 7204501 RGD 
dilated cardiomyopathy  IMP 7204501 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Egfr  (epidermal growth factor receptor)

Genes (Mus musculus)
Egfr  (epidermal growth factor receptor)

Genes (Homo sapiens)
EGFR  (epidermal growth factor receptor)


Additional Information