Activation of the tamoxifen derivative metabolite E to form DNA adducts: comparison with the adducts formed by microsomal activation of tamoxifen.
(Z)-1,2-Diphenyl-1-(4-hydroxyphenyl)but-1-ene (metabolite E) has been detected in the plasma of patients treated with tamoxifen. We therefore investigated whether the cis/trans isomers of metabolite E can be activated to form DNA adducts detected by 32P postlabeling. Microsomal activation of metabolite E produced two major (a and b) and up to six minor DNA adducts. Activation with horseradish peroxidase or silver(I)oxide produced the same adducts (a and b). Microsomal activation of tamoxifen produced one major (no. 6) and several minor DNA adducts. Rechromatography showed that adducts a and b formed by enzymatic and chemical activation of metabolite E were the same as adducts 9 and 4 produced by microsomal activation of tamoxifen. These results demonstrate that activation of metabolite E can lead to DNA adduct formation.
Pongracz
K
K
Brain Tumor Research Center, School of Medicine, University of California, San Francisco 94143, USA.
Pathak
D N
DN
Nakamura
T
T
Burlingame
A L
AL
Bodell
W J
WJ
D000475:Alkenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D001711:Biotransformation; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis*; D005260:Female; D006735:Horseradish Peroxidase / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010636:Phenols / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D013629:Tamoxifen / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000475:Alkenes; D001555:Benzene Derivatives; D018736:DNA Adducts; D010636:Phenols; D013629:Tamoxifen; D009249:NADP; C090768:1-(4-hydroxyphenyl)-1,2-diphenyl-1-butene; D004247:DNA; D006735:Horseradish Peroxidase; C007164:cumene hydroperoxide