Mutagenesis of xeroderma pigmentosum fibroblasts by acrolein

Curren, Rodger; Yang, Li; Conklin, Patricia M.; Grafström, Roland C.; Harris, Curtis C.

doi:10.1016/0165-7992(88)90104-2

Cited by 81 publications

(49 citation statements)

References 13 publications

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“…Indeed, it has been reported that Acr treatment induces significant mutations in human cells (41). Our present result also shows that Acr treatment enhances UV, BPDE, and oxidative DNA damage-induced mutagenesis.…”

Section: Discussionsupporting

confidence: 73%

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Wang

Tong

et al. 2012

Journal of Biological Chemistry

148

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Background: Acrolein is highly reactive and abundant in tobacco smoke. Results: Acrolein induces DNA damage, inhibits excision repair and mismatch repair, causes repair protein degradation, and enhances mutagenesis. Conclusion: Acrolein induces DNA damage and inhibits DNA repair that causes mutagenesis and initiates carcinogenesis. Significance: This is the first demonstration that acrolein inhibits DNA repair pathways by induction of repair protein degradation.Acrolein (Acr), a ubiquitous environmental contaminant, is a human carcinogen. Acr can react with DNA to form mutagenic ␣-and ␥-hydroxy-1, N 2 -cyclic propano-2-deoxyguanosine adducts (␣-OH-Acr-dG and ␥-OH-Acr-dG). We demonstrate here that Acr-dG adducts can be efficiently repaired by the nucleotide excision repair (NER) pathway in normal human bronchial epithelia (NHBE) and lung fibroblasts (NHLF). However, the same adducts were poorly processed in cell lysates isolated from Acr-treated NHBE and NHLF, suggesting that Acr inhibits NER. In addition, we show that Acr treatment also inhibits base excision repair and mismatch repair. Although Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes, it causes a reduction of XPA, XPC, hOGG1, PMS2, and MLH1 proteins; this effect, however, can be neutralized by the proteasome inhibitor MG132. Acr treatment further enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA but can also modify DNA repair proteins and further causes degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity.Acrolein, an ␣,␤-unsaturated aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes (1). Acr 2 is also a by-product of lipid peroxidation generated endogenously in cells under oxidative stress (2). Inhaled Acr is extremely toxic in mouse models (3). In fact, the effects of Acr on lung carcinogenicity in mouse models have not been assessed due to excessive death of Acr-exposed mice (3). Nonetheless, it has been shown that intraperitoneal injection of Acr causes bladder tumors in rat models (4 -7). Acr is a major metabolite of antitumor drugs cyclophosphamide and ifosfamide. Metabolically produced and inhaled Acr are excreted in urine and accumulated in the bladder (5, 6). It has been concluded that Acr is the culprit of bladder cancer in patients who have been administered cyclophosphamide and ifosfamide in long term treatment protocols (4 -7).Acr induces ␣-and ␥-hydroxy-1,N 2 -cyclic propano-2Ј-deoxyguanosine (␣-OH-Acr-dG and ␥-OH-Acr-dG) adducts in human cells (8). It has been found that both types of Acr-dG adducts are mutagenic and that they induce mainly G to T and G to A mutations (9 -18). By mapping Acr-dG adduct distribution at the nucleotide level in Acr-treated normal human bronchial epithelia (NHBE), we have found that the Acr-DNA binding spectrum in the p53 gene coincides with p53 mutational spectrum in lung cancer (19). Because ...

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Section: Discussionsupporting

confidence: 73%

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Wang

Tong

et al. 2012

Journal of Biological Chemistry

148

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“…1), which are mutagenic and induce predominantly G:C-to-T:A transversion mutations similar to PAHs (9). Although Acr has been shown to be cytotoxic and genotoxic in human cells, as a suspected carcinogen its carcinogenicity in animal models has not been adequately evaluated because of its extremely potent toxic effects, which often result in death (9)(10)(11). Nonetheless, it has been found that Acr treatment greatly enhances urinary bladder papilloma occurrence in rats (9).…”

Section: Dna Damagementioning

confidence: 99%

“…Unlike PAHs, where only metabolically activated forms can form adducts with DNA, Acr can directly interact with DNA and form DNA adducts (18,23). Similar to PAH-DNA adducts, Acr-DNA adducts induce mainly G:C-to-T:A transversion mutations (10,(33)(34)(35), the major type of mutations found in the p53 gene in CS-related lung cancer. Although the carcinogenicity of Acr in the lung has not been studied because of the severe toxicity associated with Acr treatment in animals, i.p.…”

Section: Acr-dg Adducts Induce G-to-t Transversion Mutations In Humanmentioning

confidence: 99%

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

Feng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

348

403

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The tumor suppressor gene p53 is frequently mutated in cigarette smoke (CS)-related lung cancer. The p53 binding pattern of carcinogenic polycyclic aromatic hydrocarbons (PAHs) found in CS coincides with the p53 mutational pattern found in lung cancer, and PAHs have thus been considered to be major culprits for lung cancer. However, compared with other carcinogenic compounds, such as aldehydes, the amount of PAHs in CS is minute. Acrolein (Acr) is abundant in CS, and it can directly adduct DNA. Acr-DNA adducts, similar to PAH-DNA adducts, induce predominantly G-to-T transversions in human cells. These findings raise the question of whether Acr-DNA adducts are responsible for p53 mutations in CS-related lung cancer. To determine the role of Acr-DNA adducts in p53 mutagenesis in CS-related lung cancer we mapped the distribution of Acr-DNA adducts at the sequence level in the p53 gene of lung cells using the UvrABC incision method in combination with ligation-mediated PCR. We found that the Acr-DNA binding pattern is similar to the p53 mutational pattern in human lung cancer. Acr preferentially binds at CpG sites, and this enhancement of binding is due to cytosine methylation at these sequences. Furthermore, we found that Acr can greatly reduce the DNA repair capacity for damage induced by benzo[a]pyrene diol epoxide. Together these results suggest that Acr is a major etiological agent for CS-related lung cancer and that it contributes to lung carcinogenesis through two detrimental effects: DNA damage and inhibition of DNA repair.DNA damage

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“…Using the 6-thioguanine resistance assay, acrolein has been shown to be nonmutagenic to Chinese hamster ovary cells (AS52; ref. 34) and normal human fibroblasts (32), whereas significant mutagenic responses have been reported in V79 Chinese hamster cells deficient in the repair of O 6 -methylguanine (35) and in human fibroblasts derived from xeroderma pigmentosum complementation group A (XP1223) deficient in nucleotide excision repair (32).…”

Section: Introductionmentioning

confidence: 99%

“…For example, acrolein has tested both positive (29) and negative (27,30) in the Ames Salmonella assays using various tester strains. Investigations of acrolein mutagenicity to mammalian cells have been limited (31)(32)(33)(34)(35); however, the scant available data point to a possible role of DNA repair in acroleininduced mutagenesis (32,35). Using the 6-thioguanine resistance assay, acrolein has been shown to be nonmutagenic to Chinese hamster ovary cells (AS52; ref.…”

Section: Introductionmentioning

confidence: 99%

Lack of Mutagenicity of Acrolein-Induced DNA Adducts in Mouse and Human Cells

2007

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Acrolein is an endogenous metabolite and a ubiquitous environmental pollutant. Recently, it has been suggested that acrolein is a major etiologic agent for tobacco smokingrelated lung cancer. Despite the known DNA-damaging effects of acrolein, its mutagenicity to mammalian cells remains uncertain. We have investigated acrolein-induced DNA damage in relation to mutagenesis, with special focus on DNA repair, in mouse and human cells. We mapped the formation of acrolein-induced DNA adducts and the kinetics of repair of the induced lesions in the cII transgene, the mutational target, in acrolein-treated transgenic mouse fibroblasts. Acrolein-DNA adducts were formed preferentially at specific nucleotide positions, mainly at G:C base pairs, along the cII transgene. The induced acrolein-DNA adducts were moderately resistant to DNA repair. Quantification of cII mutant frequency in acrolein-treated cells, however, revealed that acrolein was not mutagenic to these cells at doses sufficient to produce DNA adducts. Determination of supF mutant frequency in DNA repair-proficient and DNA repair-deficient human fibroblasts transfected with acrolein-treated plasmids confirmed a lack of acrolein mutagenicity. Because CpG methylation may intensify acrolein-DNA adduction, we examined whether the extent of CpG methylation in the supF gene can determine acroleininduced mutagenesis in human cells. Enhancement of acrolein-DNA adduction by methylating CpGs in the supF sequence did not elicit a mutagenic response in human fibroblasts, however. We conclude that acrolein is not mutagenic to mouse and human fibroblasts, regardless of DNA repair capacity or methylation status of CpGs, possibly because of a highly accurate replication bypass of the induced lesions. [Cancer Res 2007;67(24):11640-7]

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Mutagenesis of xeroderma pigmentosum fibroblasts by acrolein

Cited by 81 publications

References 13 publications

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

Lack of Mutagenicity of Acrolein-Induced DNA Adducts in Mouse and Human Cells

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