title: CYP3A4*22 is related to increased plasma levels of 4-hydroxytamoxifen and partially compensates for reduced CYP2D6 activation of tamoxifen.
abstract: OBJECTIVE
  To evaluate the impact of CYP3A4*22 in the formation of endoxifen (EDF) and hydroxytamoxifen (HTF), under different CYP2D6 genotypic backgrounds.
  
  
  METHODS
  178 patients were enrolled in the study. CYP2D6 and CYP3A4 genotyping and tamoxifen (TAM) and metabolites quantification were performed.
  
  
  RESULTS
  EDF concentrations were lower in poor (2.77 ng ml(-1)) and CYP2D6 intermediate metabolizers (5.84 ng ml(-1)), comparing to functional group (EM-F) (10.67 ng ml(-1), p < 0.001). HTF and TAM levels were respectively 47 and 53% higher in CYP3A4*22 carriers compared with *1/*1 patients in the whole group. Patients with impaired CYP2D6 metabolism and carriers of CYP3A4*22 had EDF levels comparable to CYP2D6 EM-F group (9.06 and 10.67 ng ml(-1), p = 0.247).
  
  
  CONCLUSIONS
  The presence of CYP3A4*22 might compensate the reduction of EDF concentrations related to CYP2D6 inactivity, especially due to increased HTF concentrations.
authors.affiliation: Pós-graduação em Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, n° 2400, 2nd floor, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Marina Venzon
authors.initials: MV
authors.lastname: Antunes
authors.forename: Vanessa
authors.initials: V
authors.lastname: de Oliveira
authors.forename: Suziane
authors.initials: S
authors.lastname: Raymundo
authors.forename: Dilana Elisabeth
authors.initials: DE
authors.lastname: Staudt
authors.forename: Gustavo
authors.initials: G
authors.lastname: Gössling
authors.forename: Jorge Villanova
authors.initials: JV
authors.lastname: Biazús
authors.forename: José Antônio
authors.initials: JA
authors.lastname: Cavalheiro
authors.forename: Daniela Dornelles
authors.initials: DD
authors.lastname: Rosa
authors.forename: Geneviève
authors.initials: G
authors.lastname: Mathy
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Rafael
authors.initials: R
authors.lastname: Linden
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schwartsmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood*
chemical_list: D013629:Tamoxifen; C016601:afimoxifene; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: 4-hydroxytamoxifen; CYP2D6; CYP3A4; endoxifen; genotype; tamoxifen