Activation of the tamoxifen derivative metabolite E to form DNA adducts : comparison with the adducts formed by microsomal activation of tamoxifen

• Published in: Cancer research (Chicago, Ill.) Ill.), 1995-07, Vol.55 (14), p.3012-3015
• Main Authors: PONGRACZ, K, PATHAK, D. N, NAKAMURA, T, BURLINGAME, A. L, BODELL, W. J
• Format: Article
• Language: English
• Subjects: Alkenes - metabolism; Alkenes - pharmacokinetics; Alkenes - pharmacology; Animals; Antineoplastic agents; Benzene Derivatives - pharmacology; Biological and medical sciences; Biotransformation; DNA - drug effects; DNA - metabolism; DNA Adducts - biosynthesis; Female; General aspects; Horseradish Peroxidase - metabolism; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; NADP - metabolism; Oxidation-Reduction; Pharmacology. Drug treatments; Phenols - metabolism; Phenols - pharmacokinetics; Phenols - pharmacology; Rats; Tamoxifen - metabolism; Tamoxifen - pharmacokinetics; Tamoxifen - pharmacology
• ISSN: 0008-5472; 1538-7445

(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.