Biotechnology and biopharmaceuticals : transforming proteins and genes into drugs

xxvi, 698 p.: ill.; 28 c

Novel cytochrome P450-2D6 promoter sequence variations in hepatitis C positive and negative subjects(◆)(◆)This work was supported in part by National Institutes of Health grants GM 62883, GM 32165, AI52663, AI 077390, HL 56548. RJYH was also supported by Milo Gibaldi Endowment. KVK was supported in part by NIH grant DK-02957.

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 *1/*1 (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