acrolein for mitochondria: Link between pollution, heart disease studied: Acrolein found in air, water, some foods -- GSH APOE ALA

[Guest guest]

Six cites follow the news article. Several are free online. Two report

mitochondrial effects of acrolein. Apolipoprotein E is mentioned, as is

ALA.

Furthermore, acrolein helps deplete glutathione (7). A saddingly

informative pubmed search is

glutatione AND acrolein[ti]

Often I feel as if on the deck of the Titanic, sharing news that waves

are breaking on the upper deck, waves are breaking on the upper deck,

waves are... Imaging an onboard study group focused upon /genetic

contributions to adverse effects of water engulfing the ship/.

- - - -

*

Link between pollution, heart disease studied*

*Acrolein found in air, water, some foods*

By Stahl

lstahl@...

http://www.courier-journal.com/apps/pbcs.dll/article?AID=/20080320/FEATURES03/80\

3200313

Of the 350,000 sudden cardiac deaths in the United States each year, as

many as 60,000 may be linked to pollution, according to Aruni Bhatnagar,

a University of Louisville scientist who coined the term " environmental

cardiology. "

In this relatively new field, a team of researchers at U of L is

investigating the relationship between pollution and heart disease.

Last month, at an international meeting of scientists in Boston, two U

of L researchers, Sumanth Prabhu and Conklin, discussed their

findings in separate studies.

Both studies looked at the impact of a common pollutant called acrolein,

a member of a chemical group found in air and water pollution. Acrolein

is found in automobile exhaust, tobacco smoke, beverages and some foods.

The studies were done with mice.

Prabhu's team examined the relationship between acrolein and a disease

of the heart muscle called cardiomyopathy.

The study revealed that high exposure to the pollutant caused poor heart

function. High exposure interfered with the ability of certain proteins

in the heart that help the heart muscle contract.

The team discovered that even short-term exposure to the pollutant

compromised the ability of the hearts of mice to defend against injury

during a heart attack.

When mice were exposed to the pollutant at lower levels over a longer

period of time -- this was called chronic exposure -- it changed their

hearts for the worse, causing inflammation of the heart.

" If this is proven to occur in patients, it could open up a whole new

realm for what causes heart failure, especially in those instances where

we, as physicians, don't have a very good idea of what triggered it in

the first place, " Prabhu said.

Conklin's team looked at the relationship between acrolein and the

buildup of harmful plaque in the arteries of mice.

Acrolein is particularly found in foods fried in reused oils.

Conklin said that the cholesterol of mice exposed to acrolein was

profoundly changed. Both " bad " cholesterol, called LDL, and

triglycerides went up. Exposure to the pollutant in food caused a

dramatic rise. Other mice inhaled their pollutant rather than ate it.

This caused only moderate worsening of their cholesterol profile.

Conklin said there needs to be a focus now on why acrolein in food had

such a big impact. " Does it do something to the liver or something else

that makes hardening of the arteries worse? " he asked.

Prough, a biochemist who is part of the environmental cardiology

team at U of L, said, " We know we have batteries of enzymes that get rid

of foreign compounds and naturally protect us. " One question is what

level of exposure to pollutants prevents the enzymes from being able to

do their job.

None of these impacts on mice have been proved in humans.

Bhatnagar said that two populations that appear to be most sensitive to

environmental pollutants are older people and diabetics. It is

hypothesized that perhaps their protective mechanisms decline.

Depending on their findings, scientists perhaps will one day seek to

develop a drug to help protect people who are particularly sensitive to

common pollutants such as acrolein.

Reporter Stahl can be reached at .

- - - -

1: Mol Nutr Food Res. 2008 Jan;52(1):7-25.

*Acrolein: sources, metabolism, and biomolecular interactions relevant

to human health and disease.*

s JF, Maier CS.

Department of Pharmaceutical Sciences, Oregon State University,

Corvallis, OR, USA. fred.stevens@...

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 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.

PMID: 18203133

2: Toxicology. 2008 Jan 14;243(1-2):164-76. Epub 2007 Oct 10.

*

Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human

endothelial cells.*

Szadkowski A, Myers CR.

Department of Pharmacology and Toxicology, Medical College of Wisconsin,

8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Acrolein is a reactive aldehyde that is a widespread environmental

pollutant and can be generated endogenously from lipid peroxidation. The

thioredoxin (Trx) system in endothelial cells plays a major role in the

maintenance of cellular thiol redox balance, and is critical for cell

survival. Normally, cells maintain the cytosolic (Trx1) and

mitochondrial (Trx2) thioredoxins largely in the reduced state. In human

microvascular endothelial cells, Trx1 was more sensitive than Trx2 to

oxidation by acrolein. A 30-min exposure to 2.5 microM acrolein caused

partial oxidation of Trx1 but not Trx2. The active site dithiol of Trx1

was essentially completely oxidized by 5 microM acrolein whereas 12.5

microM was required for complete oxidation of Trx2. Partial recovery of

the Trx1 redox status was observed over a 4h acrolein-free recovery

period, with increases in the reduced form and decreases in the fully

oxidized form. For cells treated with 2.5 or 5 microM acrolein the

recovery did not require protein synthesis, whereas protein synthesis

was required for the return of reduced Trx1 in cells treated with 12.5

microM acrolein. Pretreatment of cells with N-acetylcysteine (NAC)

resulted in partial protection of Trx1 from oxidation by acrolein. In

cells treated with acrolein for 30 min, followed by a 14- to 16-h

acrolein-free period, small but significant cytotoxic effects were

observed with 2.5 microM acrolein whereas all cells were adversely

affected by >or= 12.5 microM. NAC pretreatment significantly decreased

the percentage of stressed cells subsequently exposed to 5 or 12.5

microM acrolein. Given the critical role of the thioredoxins in cell

survival, the ability of acrolein to oxidize both thioredoxins should be

taken into account for a thorough understanding of its cytotoxic effects.

PMID: 18023956

3: Chem Res Toxicol. 2007 Sep;20(9):1315-20. Epub 2007 Jul 27.

*Kinetics and mechanism of protein tyrosine phosphatase 1B inactivation

by acrolein.*

Seiner DR, LaButti JN, Gates KS.

Department of Chemistry, University of Missouri, Columbia, MO 65211,

USA. gatesk@...

Human cells are exposed to the electrophilic alpha,beta-unsaturated

aldehyde acrolein from a variety of sources. The reaction of acrolein

with functionally critical protein thiol residues can yield important

biological consequences. Protein tyrosine phosphatases (PTPs) are an

important class of cysteine-dependent enzymes whose reactivity with

acrolein previously has not been well-characterized. These enzymes

catalyze the dephosphorylation of phosphotyrosine residues on proteins

via a phosphocysteine intermediate. PTPs work in tandem with protein

tyrosine kinases to regulate a number of critically important mammalian

signal transduction pathways. We find that acrolein is a potent

time-dependent inactivator of the enzyme PTP1B ( k inact = 0.02 +/-

0.005 s (-1) and K I = 2.3 +/- 0.6 x 10 (-4) M). The enzyme activity

does not return upon gel filtration of the inactivated enzyme, and

addition of the competitive phosphatase inhibitor vanadate slows

inactivation of PTP1B by acrolein. Together, these observations suggest

that acrolein covalently modifies the active site of PTP1B. Mass

spectrometric analysis reveals that acrolein modifies the catalytic

cysteine residue at the active site of the enzyme. Aliphatic aldehydes

such as glyoxal, acetaldehyde, and propanal are relatively weak

inactivators of PTP1B under the conditions employed here. Similarly,

unsaturated aldehydes such as crotonaldehyde and 3-methyl-2-butenal

bearing substitution at the alkene terminus are poor inactivators of the

enzyme. Overall, the data suggest that enzyme inactivation occurs via

conjugate addition of the catalytic cysteine residue to the

carbon-carbon double bond of acrolein. The results indicate that

inactivation of PTPs should be considered as a possible contributor to

the diverse biological activities of acrolein and structurally related

alpha,beta-unsaturated aldehydes.

PMID: 17655273

4: Biochemistry. 2007 Jul 17;46(28):8392-400. Epub 2007 Jun 20.

*Modification by acrolein, a component of tobacco smoke and age-related

oxidative stress, mediates functional impairment of human apolipoprotein E.*

Tamamizu-Kato S, Wong JY, Jairam V, Uchida K, Raussens V, Kato H,

Ruysschaert JM, Narayanaswami V.

Center for the Prevention of Obesity, Cardiovascular Disease and

Diabetes, Children's Hospital Oakland Research Institute, 5700

Luther King Jr. Way, Oakland, California 94609, USA.

Oxidative damage to proteins such as apolipoprotein B-100 increases the

atherogenicity of low-density lipoproteins (LDL). However, little is

known about the potential oxidative damage to apolipoprotein E (apoE),

an exchangeable antiatherogenic apolipoprotein. ApoE plays an integral

role in lipoprotein metabolism by regulating the plasma cholesterol and

triglyceride levels. Hepatic uptake of lipoproteins is facilitated by

apoE's ability to bind with cell surface heparan sulfate proteoglycans

and to lipoprotein receptors via basic residues in its 22 kDa N-terminal

domain (NT). We investigated the effect of acrolein, an aldehydic

product of endogenous lipid peroxidation and a tobacco smoke component,

on the conformation and function of recombinant human apoE3-NT. Acrolein

caused oxidative modification of apoE3-NT as detected by Western blot

with acrolein-lysine-specific antibodies, and tertiary conformational

alterations. Acrolein modification impairs the ability of apoE3-NT to

interact with heparin and the LDL receptor. Furthermore,

acrolein-modified apoE3-NT displayed a 5-fold decrease in its ability to

interact with lipid surfaces. Our data indicate that acrolein disrupts

the functional integrity of apoE3, which likely interferes with its role

in regulating plasma cholesterol homeostasis. These observations have

implications regarding the role of apoE in the pathogenesis of smoking-

and oxidative stress-mediated cardiovascular and cerebrovascular diseases.

PMID: 17580963

5:

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1849926 & blobtype=pdf

Environ Health Perspect. 2007 Mar;115(3):410-5. Epub 2006 Dec 11.

*Estimating risk from ambient concentrations of acrolein across the

United States.*

Woodruff TJ, Wells EM, Holt EW, Burgin DE, Axelrad DA.

Office of Policy, Economics and Innovation, U.S. Environmental

Protection Agency, San Francisco, California 94118, USA.

tracey.woodruff@...

BACKGROUND: Estimated ambient concentrations of acrolein, a hazardous

air pollutant, are greater than the U.S. Environmental Protection Agency

(EPA) reference concentration throughout the United States, making it a

concern for human health. However, there is no method for assessing the

extent of risk under the U.S. EPA noncancer risk assessment framework.

OBJECTIVES: We estimated excess risks from ambient concentrations of

acrolein based on dose-response modeling of a study in rats with a

relationship between acrolein and residual volume/total lung capacity

ratio (RV/TLC) and specific compliance (sC(L)), markers for altered lung

function. METHODS: Based on existing literature, we defined values above

the 90th percentile for controls as " adverse. " We estimated the increase

over baseline response that would occur in the human population from

estimated ambient concentrations of acrolein, taken from the U.S. EPA's

National-Scale Air Toxics Assessment for 1999, after standard

animal-to-human conversions and extrapolating to doses below the

experimental data. RESULTS: The estimated median additional number of

adverse sC(L) outcomes across the United States was approximately 2.5

cases per 1,000 people. The estimated range of additional outcomes from

the 5th to the 95th percentile of acrolein concentration levels across

census tracts was 0.28-14 cases per 1,000. For RV/TLC, the median

additional outcome was 0.002 per 1,000, and the additional outcome at

the 95th percentile was 0.13 per 1,000. CONCLUSIONS: Although there are

uncertainties in estimating human risks from animal data, this analysis

demonstrates a method for estimating health risks for noncancer effects

and suggests that acrolein could be associated with decreased

respiratory function in the United States.

PMID: 17431491

6: http://www.iovs.org/cgi/content/full/48/1/339

Invest Ophthalmol Vis Sci. 2007 Jan;48(1):339-48.

*Acrolein, a toxicant in cigarette smoke, causes oxidative damage and

mitochondrial dysfunction in RPE cells: protection by ®-alpha-lipoic

acid.*

Jia L, Liu Z, Sun L, SS, Ames BN, Cotman CW, Liu J.

Children's Hospital Oakland Research Institute, Oakland, California, USA.

PURPOSE: To understand better the cell and molecular basis for the

epidemiologic association between cigarette smoke, oxidant injury, and

age-associated macular degeneration, the authors examined the effects of

acrolein, a major toxicant in cigarette smoke, on oxidative

mitochondrial damage in retinal pigment epithelial (RPE) cells and the

reduction of this damage by lipoic acid. METHODS: Cultured human ARPE19

cells and primary cultures of human fetal (hf)RPE were treated with

acrolein. The toxicity of acrolein and the protective effects of

R-alpha-lipoic acid were examined with a variety of previously described

techniques. RESULTS: Acute acrolein exposure exceeding 50 microM (24

hours) in ARPR19 cells caused toxicity, including decreases in cell

viability, mitochondrial potential, GSH, antioxidant capacity, Nrf2

expression, enzyme activity (mitochondrial complexes I, II, III;

superoxide dismutase; and glutathione peroxidase). Acute exposure also

increased oxidant levels, protein carbonyls, and calcium. Continuous

acrolein exposure over 8 or 32 days caused similar toxicity but from 10-

to 100-fold lower doses (0.1-5 microM). Pretreatment with R-alpha-lipoic

acid effectively protected ARPE-19 cells from acrolein toxicity. Primary

hfRPE cells were comparable to the ARPE-19 cells in sensitivity to

acrolein toxicity and lipoic acid protection. CONCLUSIONS: These results

show that acrolein is a mitochondrial toxicant in RPE cells and that

acrolein-induced oxidative mitochondrial dysfunction is reduced by

lipoic acid. The similar sensitivity of the ARPE-19 and hfRPE cells

suggests that both models are useful for studying RPE toxicity and

protection. These experiments indicate that mitochondria-targeted

antioxidants such as lipoic acid may be an effective strategy for

reducing or preventing chronic oxidant-induced RPE degeneration in vivo

from a variety of sources, including cigarette smoke.

PMID: 17197552

7: http://toxsci.oxfordjournals.org/cgi/content/full/57/1/6

Toxicol Sci. 2000 Sep;57(1):6-15.

The molecular effects of acrolein.

Kehrer JP, Biswal SS.

Division of Pharmacology and Toxicology, College of Pharmacy, The

University of Texas at Austin, Austin, Texas 78712, USA.

keherjim@...

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde

to which humans are exposed in a variety of environmental situations,

particularly as a component of smoke. In addition, as a metabolite of

cyclophosphamide, acrolein is a major factor in the toxicity and perhaps

the therapeutic activity of this important anticancer agent. The

exposures to acrolein that are attained in vivo in most situations are

quite low and the effects may differ from those seen at acutely toxic

doses. At low doses, acrolein inhibits cell proliferation without

causing cell death and may enhance apoptosis from secondary toxins,

while at higher doses oncosis ensues. Although the acute toxicology of

acrolein has been extensively investigated, both in animals and cultured

cells, little information exists on the molecular effects of this

reactive aldehyde. It is possible that the acrolein-mediated decrease in

cell proliferation is caused by effecting changes in the expression of

one or more growth- or stress-related genes or transcription factors

secondary to a reduction in glutathione (GSH), which is rapidly depleted

following acrolein treatment. It is apparent that the activation of the

transcription factors nuclear factor kappa B (NF-kappa and activator

protein 1 (AP-1) can be inhibited by acrolein. The purpose of this

review is to assess the literature currently available on the molecular

effects of acrolein, to discuss the relationship between effects on

glutathione with those on various genes, and to present some new data

showing that acrolein actively stimulates genes associated with the

electrophile response element.

PMID: 10966506

*

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