Stilbene estrogen produces higher levels of mitochondrial DNA adducts thannuclear DNA adducts in the target organ of cancer (liver) of male Sprague Dawley rats

We have previously demonstrated that diethylstilbestrol is metabolized to d iethylstilbestrol reactive metabolites by mitochondrial enzymes in vitro. I n vitro, these reactive intermediates bind to mitochondrial DNA. Here we ha ve investigated the in vivo formation of diethylstilbestrol adducts with mi tochondrial DNA and the nature of mitochondrial DNA-diethylstilbestrol addu cts. Diethylstilbestrol exposure to male rats produced several adducts in m itochondrial DNA of both kidney and liver. The total relative adduct levels were 7-fold higher in mitochondrial DNA than in nuclear DNA in the target organ of cancer (liver) of Sprague Dawley rats. The chromatographic mobilit y of mitochondrial DNA adducts formed in vivo were similar to that of dGMP- DES quinone adducts formed in vitro. These findings suggest that mitochondr ial DNA appears more susceptible to formation of diethylstilbestrol adducts than nuclear DNA, and the results suggest that obstruction of replication and/or transcription of the mitochondrial genes by covalent modifications o f the mitochondrial DNA by diethylstilbestrol may produce mitochondrial gen omic instability in vivo and may provide an explanation for the carcinogeni c effects of DES.