Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

Henrik Dimke, Jenny van der Wijst, Todd R Alexander, Inez M J Meijer, Gemma M Mulder, Harry van Goor, Sabine Tejpar, Joost G Hoenderop, René J Bindels

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg(2+) transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg(2+) homeostasis, however, remains unknown. Here, we injected C57BL/6 mice with erlotinib for 23 days and observed a small but significant decrease in serum Mg(2+) concentrations at days 16 and 23, but the fractional excretion of Mg(2+) remained unchanged after 23 days. Semiquantitative immunohistochemical evaluation did not reveal detectable changes in renal expression of transient receptor potential melastatin 6 (TRPM6) protein, the channel that mediates Mg(2+) reabsorption. Patch clamp analysis in TRPM6-expressing cells demonstrated that 30 muM erlotinib inhibited EGF-induced changes in TRPM6 current density and tyrosine phosphorylation of EGFR; 0.3 muM erlotinib did not have these effects. Furthermore, 30 muM erlotinib inhibited EGF-stimulated increases in the mobile fraction of endomembrane TRPM6 channels. In summary, erlotinib can influence Mg(2+) handling but its effect on the systemic Mg(2+) concentration seems less potent than that observed with antibody-based EGFR inhibitors. These data suggest that typical human dosages of erlotinib are unlikely to severely affect serum Mg(2+) concentrations.
OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology
Vol/bind21
Udgave nummer8
Sider (fra-til)1309-16
ISSN1046-6673
DOI
StatusUdgivet - aug. 2010
Udgivet eksterntJa

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