Cisplatin-induced
ototoxicity, an important dose-limiting side effect, has proven high interindividual variability.
Glutathione S-
transferases (
GSTs) are
isoenzymes involved in cellular detoxification processes.
Megalin has been demonstrated to bind
aminoglycosides, known to be similar to
cisplatin for their
ototoxicity. The
GSTs and
megalin expression is genetically polymorphic, which might be responsible for the variability in
cisplatin-induced
ototoxicity. The genotyping of GSTM1, GSTT1 polymorphisms, and 2 nonsynonymous single nucleotide polymorphisms (SNPs) at
megalin genes, rs2075252 and rs2228171, were performed in 68 children diagnosed with solid
tumors who received
cisplatin-based
chemotherapy. After the end of treatment, audiometry demonstrated
hearing loss in 79.4% of patients according to Brock classification. The cumulative
cisplatin dose >400 mg/m is associated with increased risk of
cisplatin-induced
ototoxicity [odds ratio (OR), 17.5; 95% confidence interval (CI), 3.09-98.62]. GSTT1 wild genotype and C-allele of rs2228171 SNPs of
megalin gene occurred with higher frequency in patients with
ototoxicity (P=0.023; OR, 10; 95% CI, 1.80-56.00 and P=0.034; OR, 2.67; 95% CI, 1.22-5.82, respectively). In conclusion, our results suggested that GSTT1 wild genotype and C-allele of rs2228171 SNPs might be risk factors for
ototoxicity. The cumulative
cisplatin dose <400 mg/m should be beneficial in order to ameliorate
ototoxicity.