The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction.
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.
Department of Biochemistry & Molecular Biology, Division of Experimental Medicine, The George Washington University, Washington, DC 20037, USA. wweg@gwu.edu
William B
WB
Weglicki
Jay H
JH
Kramer
Christopher F
CF
Spurney
Joanna J
JJ
Chmielinska
I Tong
IT
Mak
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002118:Calcium / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004452:Echocardiography / Q000187:drug effects* / Q000379:methods / Q000706:statistics & numerical data; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000097:blood; D008297:Male; D018384:Oxidative Stress; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015499:Renal Tubular Transport, Inborn Errors / Q000097:blood / Q000139:chemically induced*; D013481:Superoxides / Q000097:blood; D020032:Tyrphostins / Q000009:adverse effects*
D015415:Biomarkers; D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; D013481:Superoxides; C101044:RTKI cpd; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; C483803:Egfr protein, rat; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D005978:Glutathione; D002118:Calcium