Peroxidase-mediated binding of diethylstilbestrol analogs to DNA in vitro: a possible role for a phenoxy radical.
In order to investigate the role of peroxidase-mediated metabolic activation in the mechanism of carcinogenicity of diethylstilbestrol (DES), a series of 14C-labelled analogs of DES was synthesized and their binding to DNA upon oxidation by peroxidases from horseradish or mouse uterus was studied in vitro. The compounds chosen for this study were the erythro and threo form of hexestrol (HES), the E,E- and Z,Z-isomer of dienestrol (DIES) and the mono- and dimethyl ether of DES. Non-extractable binding to DNA was observed for all compounds with at least one free hydroxyl group independent of the stilbene structure. The extent of binding was highest for the HES isomers and for E,E-DIES, whereas Z,Z-DIES and the monomethyl ether were bound to about the extent of DES. These findings imply that the formation of a phenoxy free radical is sufficient for non-extractable DNA binding and the stilbene structure is not required for peroxidase-mediated activation of DES.
D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002849:Chromatography, Gas / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004247:DNA / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D005260:Female; D005609:Free Radicals; D008401:Gas Chromatography-Mass Spectrometry; D006735:Horseradish Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007553:Isotope Labeling; D051379:Mice; D010544:Peroxidases / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism*; D013237:Stereoisomerism; D014599:Uterus / Q000201:enzymology
D002250:Carbon Radioisotopes; D005609:Free Radicals; D010636:Phenols; C042329:phenoxy radical; D004054:Diethylstilbestrol; D004247:DNA; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D010544:Peroxidases