title: Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity.
abstract: OBJECTIVE
  To characterize the interindividual variability and the individual CYP involved in the formation of alpha-hydroxy-, N-desmethyl- and N-didesmethyl-tamoxifen from tamoxifen.
  
  
  METHODS
  Microsomes from 50 human livers were used to characterize the interindividual variability in the alpha-hydroxylation, N-desmethylation and N-didesmethylation of tamoxifen. Selective inhibitors and recombinant enzymes were used to identify the forms of CYP catalysing these reactions.
  
  
  RESULTS
  The rates of formation of alpha-hydroxy-, N-desmethyl- and N-didesmethyl-tamoxifen were highly variable, and correlated with each other (P < 0.0001). The respective ranges were 0.7-11.4, 25.7-411, and below the limit of quantification--4.4 pmol mg(-1) protein min(-1). Formation of all metabolites was observed with expressed recombinant CYP3A4, inhibited by troleandomycin (65, 77 and 35%, respectively, P < 0.05) and associated with CYP3A4 expression (rs = 0.612, rs = 0.585 and rs = 0.430, P < 0.01, respectively).
  
  
  CONCLUSIONS
  Formation of alpha-hydroxy-, N-desmethyl- and N-didesmethyl-tamoxifen in vitro is highly variable and mediated predominantly by CYP3A4.
authors.affiliation: Dr Margarete Fischer-Bosch Institut für Klinische Pharmakologie, Auerbachstr. 112, D-70376 Stuttgart, Germany. janet.coller@adelaide.edu.au
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.forename: Niels
authors.initials: N
authors.lastname: Krebsfaenger
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.forename: Renzo
authors.initials: R
authors.lastname: Wolbold
authors.forename: Andreas
authors.initials: A
authors.lastname: Nüssler
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mürdter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C122072:N,N-didesmethyltamoxifen; D013629:Tamoxifen; C016601:afimoxifene; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C028787:N-desmethyltamoxifen