Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.

Riedemann L, Lanvers C, Deuster D, Peters U, Boos J, Jürgens H, Zehnhoff-Dinnesen AA

Abstract

Ototoxicity and nephrotoxicity are dose-limiting side effects of cisplatin. Megalin, a member of the low-density lipoprotein receptor family, is highly expressed in renal proximal tubular cells and marginal cells of the stria vascularis of the inner ear - tissues, which accumulate high levels of platinum-DNA adducts. On the assumption that the mechanisms of cisplatin-induced nephro- and ototoxicity involve megalin we analyzed the incidence of the non-synonymous single nucleotide polymorphisms (SNP) rs2075252 and rs4668123 in 25 patients who developed a distinct hearing loss during cisplatin therapy and in 25 patients without hearing impairment after cisplatin therapy. We found no association between cisplatin-induced ototoxicity and any allele of rs4668123 but observed a higher frequency of the A-allele of rs2075252 in the group with hearing impairment than in the group with normal hearing after cisplatin therapy (0.32 versus 0.14) (chi(2)=5.83, P<0.02; odds ratio: 3.45; 95% confidence interval: 1.11-11.2) indicating that SNPs at the megalin gene might impact the individual susceptibility against cisplatin-induced ototoxicity.The Pharmacogenomics Journal (2008) 8, 23-28; doi:10.1038/sj.tpj.6500455; published online 24 April 2007.

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