Reactivity of 4′, 4″-diethylstilbestrol quinone, a metabolic intermediate of diethylstilbestrol

Abstract

In a search for the carcinogenic metabolite of diethylstilbestrol, the interactions of 4′, 4″-diethylstilbestrol quinone with peptides and nucleic acids were investigated. Non-extractable binding of 4′, 4″-diethylstilbestrol quinone to calf thymus DNA or poly G were observed. However, adduct nu-cleosides could not be isolated subsequent to enzymatic digestion of nuclek acids. Binding to dGMP or dAMP also occurred, but the initially bound stObene estrogen could mostly be extracted with 18 extractions using various organic solvents. Non-covalent interactions of 4′, 4″-diethylstilbestrol quinone with calf thymus DNA were observed spectrally only after exhaustive dialysis of the DNA versus water, but not with native DNA. In chemical reactions of 4′, 4″-diethylstil-bestrol quinone and nucleosides, nucleotides, and amines such as n-pentyl amine, only Z, Z-dienestrol could be identified as reaction product, lite quinone did react with mercaptoethanol via Michael addition to the unsaturated carbonyl system to form a stable adduct, 4-(2-hydroxyethylthio)-3, 4-di(p-hydroxyphenyO-2-hexene. It also reacted covalently with sulfur-containing peptides such as reduced ghitathione or bovine serum albumin. Partially purified rat liver cytochrome P-450 reductase reduced 4′, 4″-diethylstilbestrol quinone to E- and Z-diethylstilbestrol. It is proposed that 4′, 4″-diethyl-stilbestrol quinone forms unstable adduct intermediates with DNA which decompose with time. Also, covalent binding of 4′, 4″-diethylstiIbestrol quinone to important proteins via thio-ether linkages may play a role in carcinogenesis.