The Correlation between CYP3A4 Genetic Polymorphism and Children with Acute Leukemia.

The aim of this study was to clarify the characteristic distribution patterns of the cytochrome P450-3A4 gene(CYP3A4)activity and the genotype of CYP3A4*1B or CYP3A4*3 in Chinese children with acute leukemia and in healthy control, and then explore whether the polymorphism of CYP3A4 is related to vulnerability to childhood leukemia and the response to chemotherapy. High performance liquid chromatography (HPLC) was used to detect the activity of CYP3A4 in 120 acute leukemia children and 85 healthy children (control group), PCR-RFLP and DNA sequencing was applied to assay their genotypes, then the difference of phenotypes and genotypes of CYP3A4 was compared between these two groups. The change scope of CYP3A4 activity was very large in children with acute lymphoblastic leukemia, from 2.00 to 585.72, the average activity was 53.52, with no dfference in sex and age. According to the clinical risk degree, the activity of CYP3A4 was 4.87±2.93 in standard-risk group, it was 31.63±19.20 in middle-risk group, the latter was significantly higher thanthe former (P=0.0004). The average CYP3A4 activity in children with acute myelocytic leukemia (AML) was 13.97±10.84. Of them, it was 15.09±7.52 in AML children with diploid chromosome and only 2.95±1.39 in hypodiploidy group, obviously, the activity of former group higher than that of latter group (P=0.0132). The CYP3A4 activity was respectively 19.78±11.59 and 2.86±1.16 in normal LDH group and in increased LDH group, there was significant difference (P=0.0036). The AML children with exo-marrow infiltration when diagnosis, their CYP3A4 activity (6.50±3.05) was lower than those children with pure marrow infiltration (19.06±11.15), P=0.044. In 85 healthy children, only one child was heterozygotic genotype of CYP3A4*1B, others were all in wild type, the mutation frequency of heterozygote was 1.2%. While in 120 children with acute leukemia, five children (including four cases with ALL and one case with AML) presented heterozygotic genotype of CYP3A4*1B, one ALL child was homozygote genotype, the mutation frequency of heterozygote was 4.2% and the frequency of homozygote was 0.8%. Convinced by PCR-RFLP and DNA sequencing, the genotype of CYP3A4*3 was in wild type in all subjects. Increased CYP3A4 activity has closed correlation with ALL risk factors. The general CYP3A4 activity in AML children group was lower than that of ALL chlidren group. Much higher or much lower CYP3A4 activity may produce adverse influence to individuals. Although the mutation frequency of CYP3A4*1B in children with acute leukemia was higher than that of in healthy control, still there was no significant, thus it could not infer that the genotype of CYP3A4*1B was correlated with the leukemogenesis in Chinese children. As CYP3A4*3 gene was a rare allele in Chinese healthy children and children with leukemia, its effect on CYP3A4 activity and leukemogenesis remains to be further investigation.