title: Cytochrome P450 polymorphisms and the response of lupus nephritis to cyclophosphamide therapy.
abstract: OBJECTIVE
  The addition of cyclophosphamide to corticosteroids significantly improves the prognosis of severe kidney involvement in systemic lupus erythematosus (SLE). However, not all patients respond to cyclophosphamide. It has been suggested that genetic variations that reduce the metabolism of cyclophosphamide reduce its effectiveness. Cyclophosphamide is metabolized and activated by the cytochrome P450 (CYP) system and in particular CYP enzymes 2B6 and 2C19. Both CYP2B6 and CYP2C19 have variant alleles (CYP2B6*5 and CYP2C19*2) that attenuate or eliminate enzymatic activity. This investigation was done to determine the impact of CYP2B6*5 and CYP2C19*2 on the renal response in cyclophosphamide-treated lupus nephritis (LN) patients.
  
  
  METHODS
  Patients with SLE (n = 237), unclassified autoimmune disease (n = 51), and healthy controls (n = 294) were genotyped for CYP2B6*5 and CYP2C19*2. Associations between these alleles and achievement of complete or partial response, development of end-stage renal disease, and time to remission were determined.
  
  
  RESULTS
  The frequencies of the variant alleles CYP2B6*5 and CYP2C19*2 were 6.3 % and 15.9%, respectively. CYP2C19*2 genotypes were more frequent among African Americans than European Americans, and CYP2B6*5 genotypes were more frequent among European Americans than African Americans. Among LN patients treated with cyclophosphamide (n = 36), there were no differences between those with or without these genotypes relative to the frequency of complete or partial remissions or time to remission.
  
  
  CONCLUSIONS
  This retrospective analysis failed to show an association between CYP2B6*5 and CYP2C19*2 and treatment outcomes in LN. This suggests that genotyping for these CYP450 variants may not be useful in individualizing treatment for severe LN.
authors.affiliation: Department of Internal Medicine, Nephrology Division and 2Department of Statistics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: J
authors.initials: J
authors.lastname: Winoto
authors.forename: H
authors.initials: H
authors.lastname: Song
authors.forename: C
authors.initials: C
authors.lastname: Hines
authors.forename: H
authors.initials: H
authors.lastname: Nagaraja
authors.forename: B H
authors.initials: BH
authors.lastname: Rovin
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies
chemical_list: D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D010089:Oxidoreductases, N-Demethylating