Co-chromatography of a tamoxifen epoxide-deoxyguanylic acid adduct with a major DNA adduct formed in the livers of tamoxifen-treated rats.
Tamoxifen is a potent liver carcinogen in rats and has been shown to form covalent DNA adducts in the livers of several species of rodent. We have shown previously by 32P-postlabeling (Carcinogenesis, 13, 2197-2203) that > 85% of the total adducts detected and resolved by multi-directional TLC migrate as a single spot. In the present study, this material was further analysed by reverse-phase HPLC and resolved into two approximately equal components. Tamoxifen 1,2-epoxide, a postulated metabolite of tamoxifen, was reacted with DNA and polydeoxyribonucleotides and the products analysed. 32P-Postlabeling revealed three major adduct spots on TLC which comigrated with the three major adduct spots seen with DNA from livers of tamoxifen-treated rats. Moreover, the major epoxide adduct, which contained guanine as the modified base, eluted on HPLC as a single major peak coincident with one of the major peaks derived from the liver DNA of tamoxifen-treated rats. These results demonstrate that approximately 40% of the tamoxifen-DNA adducts formed in vivo are chromatographically indistinguishable with the major product of the reaction of tamoxifen epoxide with guanine residues in DNA and provide important clues to the mechanism of activation of tamoxifen to a genotoxic carcinogen.
Phillips
D H
DH
Haddow Laboratories, Institute of Cancer Research, Sutton, Surrey, UK.
Hewer
A
A
White
I N
IN
Farmer
P B
PB
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004247:DNA / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D005260:Female; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D009711:Nucleotides / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology
D003848:Deoxyguanine Nucleotides; D004852:Epoxy Compounds; D009711:Nucleotides; C087492:tamoxifen 1,2-epoxide; D013629:Tamoxifen; C077233:2'-deoxyguanylic acid; D004247:DNA