chemicals in tumorigenesis
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Publication
Journal: Carcinogenesis
December/4/1996
Abstract
A number of promutagenic exocyclic DNA adducts have recently been detected in both humans and rodents without carcinogen treatment. These observations raised questions about their origins and potential significance in carcinogenesis. In this commentary, we present our views pertaining to the in vivo sources of these cyclic adducts, specifically the cyclic propano and etheno adducts. The basis for our discussion comes mainly from the information generated through a span of more than a decade from several laboratories, including ours. This commentary summarizes the data from the chemical and biochemical studies that provide support for the hypothesis that lipid peroxidation is involved in the endogenous formation of these exocyclic adducts.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
September/1/1994
Abstract
Exocyclic adducts are unique DNA modifications resulting from binding at two sites of bases that normally are involved in hydrogen-bonding for maintaining the double-helical structure of DNA. These adducts have been shown to be formed in rodents upon exposure to carcinogens. Using a sensitive 32P-postlabeling method combined with high performance liquid chromatography, we obtained evidence that 1,N2-propanodeoxyguanosine adducts of acrolein (AdG) and crotonaldehyde (CdG) are present in the liver DNA of humans and rodents without carcinogen treatment. The identities of these adducts were verified by cochromatography with the synthetic adduct standards. Further proof of identities was obtained by conversion mediated by nuclease P1 of the labeled AdG and CdG 3',5'-bisphosphates to their corresponding 5'-monophosphates. This treatment converted the in vivo adducts into products that again cochromatographed in a characteristic pattern with the synthetic 5'-monophosphates of AdG and CdG. Using this assay, we also demonstrated the in vivo stereoselective formation of one of the AdG isomers. The estimated total levels of modification were 1.0-1.7, 0.2-1.0, and 0.3-2.0 adducts in 10(6) guanine bases in the liver DNA of mice, rats, and humans, respectively. The detection of these adducts in relatively high levels without carcinogen treatment suggests that the endogenous factors such as lipid peroxidation may be important for their formation. This study provides evidence for the presence of acrolein- and crotonaldehyde-derived exocyclic adducts as common lesions in the liver DNA of rodents and humans.
Publication
Journal: Cancer Research
February/29/1996
Abstract
Our previous study (R.G. Nath and F-L. Chung; Proc. Natl. Acad. Sci. USA, 91: 7491-7495, 1994), using a 32P postlabeling method combined with high-performance liquid chromatography specifically developed for exocyclic adducts, has shown that acrolein- and crotonaldehyde-derived 1,N2-propanodeoxyguanosine adducts (AdG and CdG, respectively) are present in the liver DNA from humans and rodents without carcinogen treatment. Those findings raised important questions regarding their role as potential endogenous DNA lesions in carcinogenesis. In this study, using a similar assay, we examined a variety of tissues from untreated rats and mice (lung, kidney, brain, breast, prostate, colon, skin, and leukocytes) and detected AdG and CdG in the DNA of these tissues. More significantly, we also obtained evidence for the presence of these adducts in the DNA of human leukocytes and mammary glands. The identities of these adducts were verified by comigration of 3', 5' -bisphosphates of the 32P-labeled adduct from DNA with the synthetic standards in a reversed-phased high-performance liquid chromatography. Additional proof of identities was provided by enzymatic conversion of AdG and CdG 3',5' -bisphosphates to the corresponding 5'-monophosphates, followed by comigration with their synthetic standards. The estimated ranges of total AdG and CdG modifications in DNA of various tissues were from 0.10 to 1.60 mumol/mol guanine for humans, based on the recoveries of external standards. This study demonstrated the ubiquity of these adducts in various tissues, suggesting their potential role as endogeneous DNA lesions in rodents and humans.
Publication
Journal: Cancer Research
February/22/1988
Abstract
The reaction of trans-4-hydroxy-2-nonenal, a major alpha, beta-unsaturated aldehyde released during lipid peroxidation, with deoxyguanosine under physiological conditions was investigated in order to assess its DNA damaging potential. This aldehyde was dissolved in tetrahydrofuran (THF) prior to addition to the reaction mixture. The results showed that structurally different adducts were formed in these reactions depending on the THF used. Using THF unprotected from light, reactions yielded adducts 1 to 6. Adduct 1 was characterized as 1,N2-ethenodeoxyguanosine (5,9-dihydro-9-oxo-3-beta-D-deoxyribofuranosylimidazo[1,2-alpha]pu rine) by its UV, proton nuclear magnetic resonance, and mass spectrum and by comparison to the corresponding guanosine and guanine adducts reported in the literature. The UV spectrum of adduct 4 was indicative of a substituted 1,N2-etheno derivative. Adducts 2,3,5, and 6 were essentially identical in UV spectra and appeared to be N2-substituted deoxyguanosine diastereomers. At room temperature adducts 2,3,5, and 6 were converted quantitatively to a single product at pH 10.5. This product was shown to be identical to 1,N2-ethenodeoxyguanosine (adduct 1). Analogous conversions to 1,N2-ethenoguanine were also observed for the corresponding guanine adducts. Using THF that had been protected from the light, however, the reactions of trans-4-hydroxy-2-nonenal with deoxyguanosine gave three major adducts, 7,8, and 9. These adducts possessed UV spectra similar to that of 1,N2-propanodeoxyguanosine and were not converted to 1,N2-ethenodeoxyguanosine upon base treatment. Evidence obtained suggests that adducts 1 to 6 were formed from the reaction of deoxyguanosine with the epoxide of trans-4-hydroxy-2-nonenal generated in the presence of hydroperoxide in the light unprotected THF, whereas adducts 7 to 9 were formed by direct Michael addition. Adducts 1 to 6 were formed presumably as a result of nucleophilic addition of the exo-amino of deoxyguanosine to the aldehydic group of the epoxide of trans-4-hydroxy-2-nonenal. Base treatment of these adducts facilitated subsequent cyclization and eliminations and finally gave 1,N2-ethenodeoxyguanosine. These results demonstrated that trans-4-hydroxy-2-nonenal readily forms adducts with deoxyguanosine either by direct Michael addition or via its epoxide formation. The facile conversion of some of these adducts to a single adduct suggests that 1,N2-ethenodeoxyguanosine may provide a simple and useful marker for assessing potential DNA damage by trans-4-hydroxy-2-nonenal and related alkenals associated with lipid peroxidation.
Publication
Journal: Carcinogenesis
June/30/1994
Abstract
A 32P-postlabeling method is described that specifically detects and quantifies the 1,N2-propanodeoxyguanosine adducts derived from acrolein (AdG) and crotonaldehyde (CdG) and 1,N2-ethenodeoxyguanosine (EdG) in DNA. These exocyclic adducts are potential DNA lesions caused by exposure to enals as environmental pollutants and as endogenous compounds. This method was developed with the use of the synthetic adduct standards of these exocyclic adducts. The assay relies on HPLC for adduct enrichment prior to labeling and for quantitation and identification after labeling. The labeling efficiencies of adducts at the 1 fmol level ranged from 74 to 96%, whereas they were only 49-60% at the 100 fmol level. This method can detect as low as 0.2 fmol of adduct and allows the detection and quantitative determination of stereoisomers of AdG and CdG. The method was validated by using a sample of enzyme digests of 180 micrograms calf thymus DNA spiked with 25 or 75 fmol of adducts, which is equivalent to 5 or 15 adducts in 10(8) nucleotides. The recovery rates of these adducts in DNA ranged from 30 to 90% at the 25 fmol level and 21 to 55% at the 75 fmol level. Similar to the labeling efficiency, a greater recovery was observed with a lower amount of adduct in DNA. Overall, this method allows the simultaneous identification and quantification of exocyclic adducts AdG, CdG and EdG in DNA. Therefore, it provides a potential tool for studies of the in vivo formation of exocyclic adducts.
Publication
Journal: Carcinogenesis
December/26/1990
Abstract
Acrolein and crotonaldehyde are alpha,beta-unsaturated carbonyl compounds that form 1,N2-propanodeoxyguanosine adducts when reacted with DNA in vitro. These compounds are mutagenic in Salmonella, and crotonaldehyde is tumorigenic in rats. This study used immunoassay and 32P-postlabeling methods to determine if acrolein and crotonaldehyde form these adducts in cultured mammalian cells. Adduct levels were highest in Chinese hamster ovary cells exposed to acrolein (1 mM) with 162 mumol adduct/mol deoxyguanosine. Crotonaldehyde (10 mM) formed adduct at a level of 75 mumol/mol deoxyguanosine. 32P-Postlabeling analysis confirmed the presence of adducts in crotonaldehyde-treated cells. Persistence studies showed that adduct levels were unchanged if the cells were cultured for 6 h before DNA isolation. Mutagenicity studies were performed to determine the biological consequences of these adducts. Mutations were not observed due to the toxicity of the compounds.
Publication
Journal: Chemical Research in Toxicology
February/9/1998
Abstract
The effects of glutathione (GSH) depletion on the in vivo formation of cyclic 1,N2- propanodexoxyguanosine adducts (AdG and CdG) as background lesions in the liver DNA of F344 rats were investigated. A group of 5 male F344 rats were given drinking water containing 30 mM L-buthionine (S,R)-sulfoximine (BSO) for 21 days, and another group of 8 rats were given only drinking water as controls. The BSO-treated rats had significantly lower weight gain than control rats. The hepatic GSH levels in the BSO-treated group were reduced by 84% as compared with the control group, from 4.43 to 0.72 mumol/g of tissue. The isomeric AdG3, CdG1, and CdG2 were detected by the 32P-postlabeling/HPLC method in the liver DNA of rats without carcinogen treatment, as we reported previously [Nath, R. G., and Chung, F.-L. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 7491-7495. Nath, R. G., et al. (1996) Cancer Res. 56, 452-456]. The mean levels (mumol/mol of guanine) for AdG3, CdG1, and CdG2 were 0.57 +/- 0.25, 0.15 +/- 0.18, and 0.16 +/- 0.22 for the control group and 1.18 +/- 1.03, 3.16 +/- 3.26, and 2.50 +/- 2.59 for the BSO group, respectively. These increases correspond to approximately 2-fold for AdG and 15-21-fold for CdG adducts. The dramatic increase in the cyclic adduct levels in rat liver DNA could have resulted mainly from GSH depletion as a result of the BSO treatment, even though other unknown effects due to the toxicity of BSO cannot be ruled out. These results suggest that GSH plays an important role in protecting the liver against cyclic propano DNA adduction and provide further support for the endogenous origin of these adducts.
Publication
Journal: Mutation research
May/21/2017
Abstract
The acrolein derived cyclic 1,N(2)-propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT116+ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA.