Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carcinogenicity of estrogens in rodents and man has been attributed to either alkylation of cellular macromolecules and/or redox-cycling, generation of active radicals and DNA damage. Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. 4-Hydroxyestradiol is a potent inducer of tumors in hamsters. Previous studies have shown that 3,4-estrone quinone (3,4-EQ) can redox-cycle and is capable of inducing exclusively single strand DNA breaks in MCF-7 breast cancer cells, as well as react with various nucleophiles including amino acids and nucleic acids to give Michael addition products. In this paper we examined the nature of the interaction of 3,4-EQ with COIII gene and analysed the estrogen-DNA adducts by 32P-post-labeling. The reaction of 3,4-EQ with the COIII gene followed by polymerase arrest assay showed several stop sites in which guanine was preferentially attacked by 3,4-EQ and, to a lesser extent, with Ade, Cyt and Thy. 32P-Post-labeling analysis of the reaction of 3,4-EQ with COIII gene gave one major adduct which was found to be identical to that obtained from reaction of dGMP with 3,4-EQ. The observation that obstruction of in vitro replication of COIII template bound to 3,4-EQ suggests that estrogen quinone adducted lesions can arrest DNA polymerase. These results indicate that 3,4-EQ may be genotoxic and may provide one possible explanation for the carcinogenic effects of estrogens.
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PMID:Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene. 921 9

We have demonstrated previously 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, the nature of mitochondrial DNA-diethylstilbestrol adducts, and the influence of diethylstilbestrol adduction on in vitro replication of a mitochondrial gene. Diethylstilbestrol administration to male hamsters produced several adducts in mitochondrial DNA of both kidney and liver. The total relative adduct levels were 5- to 6-fold higher in mitochondrial DNA than in nuclear DNA. The chromatographic mobility of mitochondrial DNA adducts formed in vivo were similar to that of dGMP-DES quinone adducts formed in vitro. The identity of mitochondrial DNA adducts formed in vivo was further confirmed as dGMP-diethylstilbestrol quinone adducts by rechromatography and cochromatography. Using a DNA polymerase arrest assay we found that the DES quinone attack on a mitochondrial respiratory gene, i.e., the gene for subunit III of cytochrome c oxidase (COIII), was specific for guanine residues that were adjacent to cytosine residues. Long-term treatment with diethylstilbestrol produced tumors in the kidney, and the level of COIII transcripts was 5- to 10-fold higher in tumor samples than age-matched control kidneys. These findings suggest that i) mitochondrial DNA appears more susceptible to formation of diethylstilbestrol adducts than nuclear DNA, ii) the DNA adducts formed by DES were predominantly with guanines, iii) the adducted bases stopped DNA polymerase-mediated in vitro replication of the COIII gene, and iv) long-term exposure of hamsters to diethylstilbestrol elevated the expression of COIII mRNA. These results suggest that obstruction of replication 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 DES-induced mitochondrial structural abnormality.
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PMID:Base sequence-specific attack of stilbene estrogen metabolite(s) on the mitochondrial DNA: implications in the induction of instability in the mitochondrial genome in the kidney of Syrian hamsters. 1125 79