Stilbene estrogen produces higher levels of mitochondrial DNA adducts than nuclear DNA adducts in the target organ of cancer (liver) of male Sprague Dawley rats.
We have previously demonstrated that diethylstilbestrol is metabolized to diethylstilbestrol reactive metabolites by mitochondrial enzymes in vitro. In vitro, these reactive intermediates bind to mitochondrial DNA. Here we have investigated the in vivo formation of diethylstilbestrol adducts with mitochondrial DNA and the nature of mitochondrial DNA-diethylstilbestrol adducts. Diethylstilbestrol exposure to male rats produced several adducts in mitochondrial 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 mobility of mitochondrial DNA adducts formed in vivo were similar to that of dGMP-DES quinone adducts formed in vitro. These findings suggest that mitochondrial 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 of the mitochondrial DNA by diethylstilbestrol may produce mitochondrial genomic instability in vivo and may provide an explanation for the carcinogenic effects of DES.
Thomas
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Environmental Toxicology Program, College of Pharmacy, Florida A&M University, Tallahassee, FL 32307-3800, USA. ronald.thomas@famu.edu
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D000818:Animals; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000378:metabolism* / Q000633:toxicity; D004968:Estrogens, Non-Steroidal / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018736:DNA Adducts; D004272:DNA, Mitochondrial; D004968:Estrogens, Non-Steroidal; D004054:Diethylstilbestrol; D004247:DNA