Effects Of Gene Polymorphism, Cimetidine And Gender On Cisplatin-induced Nephrotoxicity

OBJECTIVE:To explore the gene mutation frequency of SLC22A2gene single nucleotide polymorphism (SNP)808G/T in Chinese cancer patients through gene sequencing. The ameliorative effects of the gene mutation above and cimetidine on cisplatin nephrotoxicity in Chinese cancer patients were determined by analyzing the level changes of three renal function biomarkers between the patients with different genotypes and regimens. And the relationship between gender and cisplatin nephrotoxicity was also investigated in the patients under the same genotype and regimen.METHODS:The gene fragments of SLC22A2from the DNA of123Chinese cancer patients were amplified by polymerase chain reaction (PCR) followed by gene sequencing. According to the difference of bases in the point of808, the patients were divided into two groups:wild type(GG) and mutant group(GT/TT). Patients randomized to cisplatin alone group(n=55) and cisplatin plus cimetidine group(n=68) according to the different ways of administration. Cisplatin-induced nephrotoxicity was evaluated on the basis on the analysis of three biomarkers of renal function, SCr, BUN and cystatin C. These measurements were performed on serum samples obtained separately prior to the first administration of cisplatin (baseline) and then after chemotherapy on21day of the first course. The level changes of the three biomarkers between two measurements which were detected by Dimension AR automatic biochemical analyzer were expressed for the renal function evaluation. To investigate the effect of gender, SLC22A2gene SNP808G/T and cimetidine on cisplatin nephrotoxicity, statistical analyses were performed for the level changes of the three biomarkers between different groups.RESULTS:There were three genotypes (GG, GT, and TT) at point808of SLC22A2gene in Chinese cancer patients and the T allele frequency was14.6%, which seems to be close to the previous data in other ethnic groups. There was no statistically significant difference between any two groups in the level changes of BUN and SCr. Different gender with same genotype and regimen demonstrated no statistically significant differences in the concentration change of cystatin C, which illustrated that the gender was not associated with cisplatin nephrotoxicity. But the cystatin C level changes of the patients with mutant genotype (GT/TT) was significantly smaller than which of participants with wild genotype (GG) in the cisplatin alone group. In the wild-type patients, the cystatin C level changes in the cisplatin alone group was significantly larger than that in the cisplatin plus cimetidine group. However, this trend does not exist in patients carried mutant-type GT/TT between two different treatment groups. So we consider that the808G/T variance in the SLC22A2gene and cimetidine combination could attenuate cisplatin nephrotoxicity. But the renoprotection mechanism of cimetidine can be damaged by the mutation.CONCLUSION:The SLC22A2gene SNP808G/T exists in Chinese cancer patients and the T allele frequency was14.6%. Cystatin C served as a more sensitive clinical marker than SCr and BUN for the early assessment of renal damage caused by cisplatin. This study investigated for the first time the effects of808G/T polymorphism in the OCT2gene, cimetidine and gender on cisplatin nephrotoxicity according to the level changes of cystatin C. The gender was not associated with cisplatin nephrotoxicity. The results also indicated that the mutation of808G/T can attenuate the cisplatin nephrotoxicity and cimetidine could protect against renal injury except on the patients with the mutation of SLC22A2gene (808G/T). It is clinically relevant for prediction and protection of nephrotoxicity and individual chemotherapy through gene sequencing for chemotherapy with cisplatin.