Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients

doi:10.3969/j.issn.2095-4344.2013.05.005

Abstract

Abstract:

BACKGROUND: Cyclosporine A is metabolized mainly by cytochrome P450 3A4 (CYP3A4). Previous studies have suggested that genetic polymorphisms of CYP3A4 have an effect on the pharmacokinetics of cyclosporine A. Moreover, cyclosporine A -related chronic nephrotoxicity is caused by long-term exposure to cyclosporine A. It is conceivable that genetic polymorphisms of CYP3A4 may be responsible for the cyclosporine A-related chronic nephrotoxicity in renal transplant recipients.
OBJECTIVE: To analyze the relationship between CYP3A4 gene polymorphism and cyclosporine A- related chronic nephrotoxicity.
METHODS: A total of 200 patients (105 diagnosed as having cyclosporine A-related chronic renal toxicity through renal biopsy and (or) serum creatinine values change and 95 without nephrotoxicity) undergoing cyclosporine A therapy participated in this study. Peripheral venous blood samples were collected and genomic DNA was extracted. Mutations in exons 5, 7, 9, and 12 of the CYP3A4 gene were screened by PCR and direct DNA sequencing.
RESULTS AND CONCLUSION: Three novel mutations of CYP3A4 gene were discovered in this study, namely 336 A>G, 837 G>A and 406 A>C. The novel mutation 336 A>G was detected in three renal transplant recipients and 837 G>A was detected in eight recipients. Importantly, the novel mutation at 406A>C was detected only in three patients with cyclosporine A nephrotoxicity, and the novel mutation 406 A>C could result in the changes from 136 Threonine in the conserved region of CYP3A4 gene to phenylalanine. However, the known polymorphisms of exons 5, 7, 9, and 12 of the CYP3A4 gene were not detected in Chinese population. Three novel mutations at 336 A>G, 837 G>A and 406 A>C were detected in CYP3A4 gene in Chinese renal transplant recipients. The novel mutation at 406 A>C was predicted to change the enzyme activity of CYP3A4 enzyme.

Key words: organ transplantation, renal transplantation, chronic nephrotoxicity, cytochrome P450 3A4, cyclosporine A, new mutation, provincial grants-supported paper

CLC Number:

R318

Shi Lei, He Bao-xia, Zeng Xiao-hui, Zhu Yun-song, Zhang Hong-bin, Bao Ze-qing, Zhao Shu-jin. Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(5): 791-796.

Figures/Tables 5

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