Objective: The purpose of this study was to screen for frequencies of different CYP450 genotypes in the Chinese population and explore the relationship between sorafenib toxicity and CYP450 polymorphism.
Methods: A total of 600 peripheral blood samples were obtained from two groups for this study. The first group of 300 samples were from Chinese patients with HBV/HCV-associated HCC, while the remaining 300 samples were from a healthy population of recruited subjects. Allele-specific PCR and long-fragment gene sequencing was used to identify the frequencies of CYP450 polymorphism. Aflatoxin-induced HCC rat models expressing CYP3A4*1, CYP3A5*3, CYP2C19*2, and CYP2D6*10 were established and treated with sorafenib at certain time points. Hepatic and renal function, along with plasma concentration of sorafenib, were monitored regularly.
Results: The most common forms of CYP mutations in the Chinese population were identified. The levels of sorafenib plasma concentration, as well as damage to hepatic and renal function in aflatoxin-induced HCC rat models varied significantly across the different CYP genotypes.
Conclusion: The mutational frequencies of CYP3A5, CYP3A4, CYP2C19, and CYP2D6 genotypes varied among different ethnic groups and populations. Individuals with CYP3A5*3 demonstrated minimal sorafenib metabolism, which led to severe hepatic and renal damage. Inter-individual variability in sorafenib-toxicity may be interpreted by CYP450 genetic polymorphisms, suggesting that identification of CYP polymorphism within a certain population should be considered in sorafenib therapy.
【저자키워드】 Hepatocellular carcinoma, sorafenib., CYP450 polymorphism, Inter-individual adverse events,