Novel cytochrome P450-2D6 promoter sequence variations in hepatitis C positive and negative subjects

作者：Ho Martin T; Kelly Edward J; Bodor Miklos; Bui Tot; Kowdley Kris V; Ho Rodney J Y^*

来源：Annals of Hepatology, 2011, 10(3): 327-332.

DOI：10.1016/s1665-2681(19)31545-5

• CYP450 enzyme
• Genotype
• Phenotype
• Genetic variant
• Hepatitis

Introduction. CYP2D6 is a liver enzyme that metabolizes more that 25% of drugs and thus may play a pivotal role in drug-drug interactions. The promoter sequences of cytochrome P450 2D6 (CYP2D6) gene could impact metabolic activity. Methods. We analyzed genetic variations in the promoter sequence of CYP2D6 gene for 71 hepatitis C negative and 15 hepatitis C positive subjects. Results. We found two novel genetic variants -1822A -> G; -1740C -> T, only in two patients with hepatitis C. Also, two linked new promoter sequence variations at -2060 G -> A and -2053 T -> G nucleotide positions that present in both hepatitis C negative and positive subjects are identified. The -2060 and -2053 variations are confirmed to be in linkage disequilibrium. The individuals with -2060A/A, and -2053G/G variation appeared to be associated with significantly lower levels of liver CYP2D6 mRNA. Analysis of CYP2D6 enzymatic activity in *11 (wild type) subjects revealed that hepatitis C positive subjects expressed about 2.6-fold lower activity (24.0 +/- 1.5 vs. 62.6 +/- 3.7 pmol/min/mg; p = 0.0061) relative to hepatitis C negative. Conclusion. These data suggest that promoter variations -1822A -> G and -1740C -> T are present only in hepatitis C infected subjects. Hepatitis C positive individuals were associated with a lower liver CYP2D6 enzyme activity.

• 出版日期2011-9