Determination of toxic carbonyl compounds in cigarette smoke

Fujioka, Kazutoshi; Shibamoto, Takayuki

doi:10.1002/tox.20153

Cited by 169 publications

(147 citation statements)

References 35 publications

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“…72,73 Cigarette smoke is implicated in these aggregates in humans with chronic obstructive pulmonary disease. 72 Because our study demonstrates that diacetyl alters proteostasis and cigarette smoke contains diacetyl, 74,75 the results suggest that diacetyl may play a role in chronic obstructive pulmonary disease in addition to its role in flavorings-related lung disease. 11,12 In addition, during autophagy, SQSTM1 is phosphorylated, a process that activates the Kelch-like ECHassociated protein 1 (Keap1)enuclear factor E2erelated factor 2 (Nrf2) pathway.…”

Section: Protein Damage and Diacetyl Cytotoxicitymentioning

confidence: 82%

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Hubbs

Fluharty

Edwards

et al. 2016

The American Journal of Pathology

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Inhaled diacetyl vapors are associated with flavorings-related lung disease, a potentially fatal airway disease. The reactive a-dicarbonyl group in diacetyl causes protein damage in vitro. Dicarbonyl/ L-xylulose reductase (DCXR) metabolizes diacetyl into acetoin, which lacks this a-dicarbonyl group. To investigate the hypothesis that flavorings-related lung disease is caused by in vivo protein damage, we correlated diacetyl-induced airway damage in mice with immunofluorescence for markers of protein turnover and autophagy. Western immunoblots identified shifts in ubiquitin pools. Diacetyl inhalation caused dose-dependent increases in bronchial epithelial cells with puncta of both total ubiquitin and K63-ubiquitin, central mediators of protein turnover. This response was greater in Dcxr-knockout mice than in wild-type controls inhaling 200 ppm diacetyl, further implicating the a-dicarbonyl group in protein damage. Western immunoblots demonstrated decreased free ubiquitin in airway-enriched fractions. Transmission electron microscopy and colocalization of ubiquitin-positive puncta with lysosomal-associated membrane proteins 1 and 2 and with the multifunctional scaffolding protein sequestosome-1 (SQSTM1/p62) confirmed autophagy. Surprisingly, immunoreactive SQSTM1 also accumulated in the olfactory bulb of the brain. Olfactory bulb SQSTM1 often congregated in activated microglial cells that also contained olfactory marker protein, indicating neuronophagia within the olfactory bulb. This suggests the possibility that SQSTM1 or damaged proteins may be transported from the nose to the brain. Together, these findings strongly implicate widespread protein damage in the etiology of flavorings-related lung disease. (Am J Pathol 2016, 186: 2887e2908; http://dx

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Section: Protein Damage and Diacetyl Cytotoxicitymentioning

confidence: 82%

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Hubbs

Fluharty

Edwards

et al. 2016

The American Journal of Pathology

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“…This treatment induced 50 to 90% of cytotoxicity in NHBE and NHLF, respectively. It should be noted that 50 M Acr is equivalent to Acr concentration in lung tissue in an individual who has smoked 10 -20 cigarettes (20). The Acr cytotoxicity was determined by WST-1 method as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

“…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 Acr is abundant in tobacco smoke and its level is up to 10,000-fold that of benzo-(a)pyrene (20,21), we concluded that Acr is a major lung carcinogen. This conclusion is consistent with the finding that lung cancer is the number one cancer death in Taiwanese women, and yet only 5% of these women are tobacco smokers and that lung cancer incidence was greatly reduced in Taiwanese women in households that were equipped with fume extractors (22)(23)(24)(25)(26).…”

mentioning

confidence: 93%

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Wang

Tong

et al. 2012

Journal of Biological Chemistry

147

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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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“…Acr is one of the most abundant compounds generated in CS; the amount of Acr in a single cigarette, depending on the manufacturer, ranges from 10 to 500 g (8,31). The total amount of PAHs present in CS, in contrast, is in the range of just a few micrograms (8).…”

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.

342

402

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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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Determination of toxic carbonyl compounds in cigarette smoke

Cited by 169 publications

References 35 publications

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

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

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