title: Novel cytochrome P450-2D6 promoter sequence variations in hepatitis C positive and negative subjects.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195-7610, USA.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ho
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kelly
authors.forename: Miklos
authors.initials: M
authors.lastname: Bodor
authors.forename: Tot
authors.initials: T
authors.lastname: Bui
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D004279:DNA, Viral; D012333:RNA, Messenger; D019389:Cytochrome P-450 CYP2D6