Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity.
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.
Coller
Janet K
JK
Dr Margarete Fischer-Bosch Institut für Klinische Pharmakologie, Auerbachstr. 112, D-70376 Stuttgart, Germany. janet.coller@adelaide.edu.au
Krebsfaenger
Niels
N
Klein
Kathrin
K
Wolbold
Renzo
R
Nüssler
Andreas
A
Neuhaus
Peter
P
Zanger
Ulrich M
UM
Eichelbaum
Michel
M
Mürdter
Thomas E
TE
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*
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