Acrolein produced from polyamines as one of the uraemic toxins

Sakata, Kumiko; Kashiwagi, Keiko; Sharmin, Shahana; Ueda, Shiro; Igarashi, Kazuei

doi:10.1042/bst0310371

Cited by 76 publications

(58 citation statements)

References 17 publications

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“…Figure 5A shows a significant increase in the ROS production as indicated by the shift to the right of the fluorescence peaks in the presence of CM-H 2 DCFDA, an oxidation-sensitive fluorescent probe. Spermine oxidation by SMO produces H 2 O 2 and 3-aminopropanal that spontaneously forms the highly reactive and toxic compound acrolein (28). Protein-conjugated acrolein levels as determined by ELISA assay were significantly elevated in Ker/ODC compared with Ker/Norm, and the accumulation of acrolein protein conjugates was prevented with DFMO treatment (Fig.…”

Section: Resultsmentioning

confidence: 86%

“…Although increased activity of polyamine catabolic oxidases, including both APAO and SMO, have been shown to lead to oxidative stress (21,22,25), our data suggest that induction of SMO is primarily responsible for the increased H 2 O 2 and acrolein accumulation in Ker/ODC. Igarashi et al (28,40) have shown that acrolein is the major toxic compound produced from spermine by SMO. We have shown by a direct ELISA assay that there is a significant increase in acrolein-conjugated lysine in Ker/ ODC cell lysates compared with Ker/Norm and that this can be blocked with DFMO.…”

Section: Discussionmentioning

confidence: 99%

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Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes

Wei

DeFeo²,

Hayes³

et al. 2008

Cancer Research

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We examined the effect of increased expression of ornithine decarboxylase (ODC), a key rate-limiting enzyme in polyamine biosynthesis, on cell survival in primary cultures of keratinocytes isolated from the skin of K6/ODC transgenic mice (Ker/ ODC) and their normal littermates (Ker/Norm). Although elevated levels of ODC and polyamines stimulate proliferation of keratinocytes, Ker/ODC undergo apoptotic cell death within days of primary culture unlike Ker/Norm that continue to proliferate. Phosphorylation of ataxia telangiectasia mutated (ATM) and its substrate p53 are significantly induced both in Ker/ODC and in K6/ODC transgenic skin. Chromatin immunoprecipitation analyses show that the increased level of p53 in Ker/ODC is accompanied by increased recruitment of p53 to the Bax proximal promoter. ATM activation is polyamine dependent because A-difluoromethylornithine, a specific inhibitor of ODC activity, blocks its phosphorylation. Ker/ ODC also displays increased generation of H 2 O 2 , acroleinlysine conjugates, and protein oxidation products as well as polyamine-dependent DNA damage, as measured by the comet assay and the expression of the phosphorylated form of the histone variant ;H2AX. Both reactive oxygen species generation and apoptotic cell death of Ker/ODC may, at least in part, be due to induction of a polyamine catabolic pathway that generates both H 2 O 2 and cytotoxic aldehydes, because spermine oxidase (SMO) levels are induced in Ker/ODC. In addition, treatment with MDL 72,527, an inhibitor of SMO, blocks the production of H 2 O 2 and increases the survival of Ker/ODC. These results show a novel activation of the ATM-DNA damage signaling pathway in response to increased ODC activity in nontumorigenic keratinocytes. [Cancer Res 2008;68(7):2214-22]

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Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes

Wei

DeFeo²,

Hayes³

et al. 2008

Cancer Research

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“…FDP-lysine (see [33]) levels were also enhanced in these patients (170 μM versus 31.2 μM, P < 0.001) [57]. These data suggest that polyamine catabolism may be a significant source of acrolein compared to lipid peroxidation.…”

Section: Polyaminesmentioning

confidence: 72%

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Stevens

Maier

2008

Molecular Nutrition Food Res

630

634

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Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.

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“…1 Results from age-matched normal and uremic patients showed that both concentrations and particularly, spermine were reduced in uremia. 53 Furthermore, there was a clear increase in both acrolein, a toxic spermine oxidation product, and in the activity of the responsible oxidase. 53 Interestingly, concentrations in malondialdehyde actually increased with CKD severity, which supports its classification as a uremic retention solute.…”

Section: Variability In Concentrationsmentioning

confidence: 99%

“…53 Furthermore, there was a clear increase in both acrolein, a toxic spermine oxidation product, and in the activity of the responsible oxidase. 53 Interestingly, concentrations in malondialdehyde actually increased with CKD severity, which supports its classification as a uremic retention solute. 22,84 Whether normal and uremic concentrations of retention solutes were comparable is a difficult aspect of this study, especially when results are drawn from different sources.…”

Section: Variability In Concentrationsmentioning

confidence: 99%

Normal and Pathologic Concentrations of Uremic Toxins

Duranton¹,

Cohen

Smet

et al. 2012

Journal of the American Society of Nephrology

826

764

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An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of b2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. The uremic syndrome is characterized by the retention of various solutes that would normally be excreted by the kidneys. The substances that interact negatively with biologic functions are called uremic toxins. In the past years, research on uremic toxicity has been very dynamic and resulted in the identification of dozens of retention solutes, including several uremic toxins. In 2003, the European Uremic Toxin Work Group (http://www.uremic-toxins.org/) proposed a classification of 90 retention solutes providing data on normal and pathologic serum concentrations. 1 In 2007, results were further discussed and expanded with the addition of 14 solutes. 2,3 This collaborative work focused on the highest mean or median concentration of the solutes measured in a uremic population and the highest individual uremic concentration. These data were particularly relevant for researchers on uremic toxicity, and they became a successful tool for allowing use of standardized and biologically relevant concentrations in experimental settings. More recently, scientific and technological progress resulted in the identification of many new uremic retention solutes, particularly thanks to nontargeted approaches such as metabolomic and proteomic profiling. 4,5 To maintain experimental guidelines in keeping with current knowledge, it seemed necessary to propose an update of the encyclopedic review.

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Acrolein produced from polyamines as one of the uraemic toxins

Cited by 76 publications

References 17 publications

Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes

Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated–DNA Damage Signaling in Normal Keratinocytes

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Normal and Pathologic Concentrations of Uremic Toxins

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