title: CYP2C19 genotype-phenotype discordance in patients with multiple myeloma leads to an acquired loss of drug-metabolising activity.
abstract: OBJECTIVE
  Previous reports indicate that discordance between CYP2C19 genotype and enzyme function occurs in up to 37 % of cancer patients with a range of solid tumours. The aim of this study was to determine whether this acquired loss of function in hepatic CYP2C19 activity also occurs in patients with haematological malignancy.
  
  
  METHODS
  CYP2C19 genotype was determined in 25 patients with multiple myeloma using PCR-RFLP analysis for the common allelic variants (*2, 681G>A, rs4244285; *3, 636G>A, rs49486893, and *17, -806C>T, rs12248560). The activity of the enzyme was evaluated using the CYP2C19 probe drug proguanil, and a metabolic ratio used to categorise subjects as extensive or poor metabolisers (PM).
  
  
  RESULTS
  No genotypic PM (homozygous null) were detected in this patient cohort. However, CYP2C19 activity was severely compromised in some multiple myeloma patients, resulting in a PM status in 28 % of subjects. Hence, there was significant (p < 0.0001) discordance between the CYP2C19 activity predicted by genotype and the measured phenotype. Discordant CYP2C19 activity did not correlate with any of the pro-inflammatory markers studied.
  
  
  CONCLUSIONS
  Acquired loss of CYP2C19 activity occurs in a substantial proportion of patients with multiple myeloma. This indicates that the previously reported phenomenon is not limited to patients with solid tumours. Thus, measurement of CYP2C19 activity rather than CYP2C19 genotype may be more clinically relevant for the determination of whether loss of CYP2C19 function adversely influences the toxicity and efficacy of certain drugs used in medical oncology.
authors: Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors: K E
authors: KE
authors: Burns
authors: M A
authors: MA
authors: Goldthorpe
authors: F
authors: F
authors: Porteus
authors: P
authors: P
authors: Browett
authors: N A
authors: NA
authors: Helsby
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D002727:Proguanil / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D002727:Proguanil