3‐Hydroxypropylmercapturic acid: A biologic marker of exposure to allylic and related compounds

Sanduja, Radhika; Ansari, Ghulam; Boor, Paul J.

doi:10.1002/jat.2550090406

Cited by 53 publications

(45 citation statements)

References 12 publications

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“…When allylamine was administered to rats by gavage (5-150 mg/kg), 44-48% of the dose was converted to acrolein by oxidative deamination and found in the urine as HPMA during the first 24 h. A small amount (3% of the dose) was excreted in the urine as HPMA in the second 24-h period. Oral administration of acrolein to rats resulted in 79% recovery as HPMA in the 0-24-h urine [74]. In another study, the sum of HPMA and CEMA excreted in the urine during the first 24 h after intraperitoneal administration of acrolein to rats (0.5-2.0 mg/kg) accounted for 29.2 ± 6.5% of the dose.…”

Section: Glutathione Conjugation With Acroleinmentioning

confidence: 93%

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

Stevens

Maier

2008

Molecular Nutrition Food Res

615

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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Section: Glutathione Conjugation With Acroleinmentioning

confidence: 93%

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

Stevens

Maier

2008

Molecular Nutrition Food Res

615

634

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“…This corresponds to findings that 78.5% of an oral dose of 13 mg acrolein/kg bw in rats was excreted as 3-HPMA. Other metabolites were not analysed [5]. Oxalic acid was only detected after oral administration.…”

Section: Introductionmentioning

confidence: 97%

Toxicology and risk assessment of acrolein in food

Abraham

Andres

Palavinskas

et al. 2011

Molecular Nutrition Food Res

143

126

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Acrolein is an α,β-unsaturated aldehyde formed by thermal treatment of animal and vegetable fats, carbohydrates and amino acids. In addition it is generated endogenously. As an electrophile, acrolein forms adducts with gluthathione and other cellular components and is therefore cytotoxic. Mutagenicity was shown in some in vitro tests. Acrolein forms different DNA adducts in vivo, but mutagenic and cancerogenous effects have not been demonstrated for oral exposure. In subchronic oral studies, local lesions were detected in the stomach of rats. Systemic effects have not been reported from basic studies. A WHO working group established a tolerable oral acrolein intake of 7.5 μg/kg body weight/day. Acrolein exposure via food cannot be assessed due to analytical difficulties and the lack of reliable content measurements. Human biomonitoring of an acrolein urinary metabolite allows rough estimates of acrolein exposure in the range of a few μg/kg body weight/day. High exposure could be ten times higher after the consumption of certain foods. Although the estimation of the dietary acrolein exposure is associated with uncertainties, it is concluded that a health risk seems to be unlikely.

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“…Our data clearly shows marked depletion of thiols in mito chondrial and postmitochondrial fractions of aorta, epicardium and endocardium as a major occurrence con comitant with toxic injury. The maximum depletion of free -SH suggests that cysteine and glutathione are exten sively used up during allylamine metabolism, as would be expected since the in vivo excretion as a mercapturic acid has been described [12]. Furthermore, our results obtained from glutathione peroxidase measurements revealed mild and transient increase only in mitochondrial fraction of aorta at 3 h. This could be a compensatory, transient response to gen eralized oxidative stress (such as the generation of HUCF occurring due to allylamine deamination), since we did not find the same response at 5 h. It appears, then, that in this case of vascular injury, the cellular defense against xenobiotic toxic injury is predominantly handled by small molecules like glutathione rather than by enzymatic de fense mechanisms (glutathione peroxidase, catalase).…”

Section: Discussionmentioning

confidence: 84%

“…Al though it is possible that such alterations may occur at later times (e.g. many hours or days), the early changes studied here are occurring during the fairly rapid time course of allylamine metabolism [7], well before its excre tion in the urine as a mercapturic acid [12], To localize the likely subcellular site of injury, we per formed a standard assay of peroxidative damage, i.e., TBARS analysis. The maximal increase in TBARS in the mitochondrial fraction of aorta, which we describe here, suggests the possibility of acute dysfunction of mitochon drial membrane in aorta.…”

Section: Discussionmentioning

confidence: 99%

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Lipid Peroxidation and Oxidative Stress during Acute Allylamine-lnduced Cardiovascular Toxicity

Awasthi

Boor²

1994

J Vasc Res

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Allylamine is an aliphatic amine that causes vascular lesions in aorta and medium-sized arteries. This primary amine has been shown to be metabolized to acrolein both in vivo and in vitro. Acrolein may cause allylamine’s toxic effects, since it acts as a strong peroxidizing agent itself; in addition, deamination of allylamine is accompanied by production of hydrogen peroxide. To investigate the relative roles of oxidative stress and lipid peroxidation in allylamine intoxication, we conducted an acute in vivo time-course study following administration of allylamine (150 mg/kg) to rats by gavage. Animals were sacrificed at 1, 3 and 5 h after allylamine treatment, and subcellular fractions of aorta, epicardium and endocardium were assayed for enzymes of the oxidant defense system and thiol (-SH) status, capacity for lipid peroxidation, and ‘OH radical generation. Results suggest that in vivo treatment with allylamine causes preferential damage to aortic mitochondria. A marked depletion of total and free -SH content was found in aorta, epicardium and endocardium, with a striking increase in the formation of thiobarbiturate-reactive substance by aortic mitochondria at all time points. A significant increase in the capacity to generate ‘OH was found in aorta (with lesser increases in epicardium and endocardium) after allylamine treatment. Levels of defense system enzymes were not consistently altered, however. In a totally in vitro experiment, liposomes incubated with acrolein (0.2–2 mM) showed a proportional increase in lipid peroxidation of liposomal membrane. A likely basis of allylamine’s cardiovascular toxicity is acrolein-induced lipid peroxidation, especially in mitochondria.

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3‐Hydroxypropylmercapturic acid: A biologic marker of exposure to allylic and related compounds

Cited by 53 publications

References 12 publications

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

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

Toxicology and risk assessment of acrolein in food

Lipid Peroxidation and Oxidative Stress during Acute Allylamine-lnduced Cardiovascular Toxicity

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