Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration

Tuma, Dean J.; Thiele, Geoffrey M.; Xu, Dongsheng; Klassen, Lynell Warren; Sorrell, Michael F.

doi:10.1002/hep.510230431

Cited by 224 publications

(146 citation statements)

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“…In addition to its DNA effects, ethanol-induced oxidant stress can modify proteins in general by enhancing the irreversible covalent binding of acetaldehyde to lysine residues. 31,32 The present finding of decreased MTHFR activity in response to both ethanol feeding and folate deficiency may constitute another explanation for low serum folate levels in chronic alcoholics. 16 However, we cannot determine whether decreased MTHFR activity resulted in selectively decreased end product 5-MTHF in the experimental groups, because folate analogs were not measured in their livers.…”

Section: Discussionmentioning

confidence: 63%

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Villanueva

Halsted

2004

Hepatology

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Alcoholic liver disease is associated with abnormal hepatic methionine metabolism, including increased levels of homocysteine and S-adenosylhomocysteine (SAH) and reduced levels of Sadenosylmethionine (SAM) and glutathione (GSH). The concept that abnormal methionine metabolism is involved in the pathogenesis of alcoholic liver disease was strengthened by our previous findings in a micropig model where combining dietary folate deficiency with chronic ethanol feeding produced maximal changes in these metabolites together with early onset of microscopic steatohepatitis and an eightfold increase in plasma aspartate aminotransferase. The goal of the present study was to determine potential mechanisms for abnormal levels of these methionine metabolites by analyzing the transcripts and activities of transmethylation enzymes in the livers of the same micropigs. Ethanol feeding or folate deficiency, separately or in combination, decreased transcript levels of methylenetetrahydrofolate reductase (MTHFR), methionine adenosyltransferase (MAT1A), glycine-N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (SAHH). Ethanol feeding alone reduced the activities of methionine synthase (MS) and MATIII and increased the activity of GNMT. Each diet, separately or in combination, decreased the activities of MTHFR and SAHH. In conclusion, the observed abnormal levels of methionine metabolites in this animal model of accelerated alcoholic liver injury can be ascribed to specific effects of ethanol with or without folate deficiency on the expressions and activities of hepatic enzymes that regulate transmethylation reactions. These novel effects on transmethylation reactions may be implicated in the pathogenesis of alcoholic liver disease. ( A bnormal hepatic methionine metabolism can result from chronic exposure to ethanol or from folate deficiency. Hyperhomocysteinemia has been described in chronic alcoholics, 1,2 and decreased liver S-adenosylmethionine (SAM) levels were found in experimental animals and cultured hepatocytes exposed to ethanol. [3][4][5][6] Folate deficiency also results in abnormal methionine metabolism, because 5-methyltetrahydrofolate (5-MTHF) is substrate for the methionine synthase (MS) reaction that converts homocysteine to methionine, the substrate for SAM (Fig. 1). Furthermore, folate deficiency is frequently associated with alcoholic liver disease, in part, because chronic exposure to ethanol reduces the intestinal transport of folic acid and increases folate excretion in the urine. [7][8][9] Previous data support the concept that changes in methionine metabolism are involved in the development of alcoholic liver disease. Studies in rats and micropigs have demonstrated MS activity is reduced during chronic ethanol exposure. 10 -13 Rats that were fed ethanol by gastric tube demonstrated decreased methionine adenosyltransferase MAT1-III activity with decreased SAM and SAM/ S-adenosylhomocysteine (SAH) ratio in association with increased DNA strand breaks. 5 A MAT1A knockout mouse model developed he...

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Section: Discussionmentioning

confidence: 63%

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Villanueva

Halsted

2004

Hepatology

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“…15,16 The chemical structure of these adducts has been characterized to some extent showing the presence of a linear adduct to the ⑀-amino group of lysine containing acetaldehyde and MDA in 1:1 ratio (2-formyl-3-alkylamino-butanol), and a cyclic adduct (4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde) where the two aldehydes are present in 2:1 ratio (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…4,21 Indeed, experiments using quantitative competitive ELISA have shown the in vivo formation of appreciable amounts of MAA protein adducts in the liver of chronically ethanol-fed rats, but not in pair-fed controls. 16 The cyclic MAA adducts have strong immunogenic properties, and treatment with MAA-modified proteins leads to the production of antibodies that specifically recognize this epitope. 15,17 Recently, Xu et al 18 have reported the presence of circulating antibodies against the cyclic adduct MAA in rats chronically exposed to alcohol.…”

Section: Discussionmentioning

confidence: 99%

“…14 Recent studies from our laboratory have shown that malonildialdehyde (MDA), a product of ethanol-induced lipid peroxidation, and acetaldehyde react together with proteins to form mixed malonildialdehyde-acetaldehyde (MAA) adducts. 15,16 One of the major MAA protein adducts has been identified as the 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde derivative of amino groups (Fig. 1).…”

mentioning

confidence: 99%

“…15 MAAprotein conjugates have strong immunogenic properties and induce the production of antibodies against both the MAA epitopes and the carrier protein. 17 MAA adducts have been detected in livers of ethanol-fed rats, 16 and their presence is associated with the development of circulating anti-MAA antibodies in alcohol-treated rats. 18 Because alcohol abuse stimulates lipid peroxidation in the liver along with acetalde-hyde production, [19][20][21][22] we have investigated the possibility that MAA antigens might also be formed in humans and contribute to the development of immunologic reactions associated with the development of ALD.…”

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confidence: 99%

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Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease

et al. 2000

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Acetaldehyde and malonildialdehyde can form hybrid protein adducts, named MAA adducts that have strong immunogenic properties. The formation of MAA adducts in the liver of chronic alcohol-fed rats is associated with the development of circulating antibodies that specifically recognized these adducts. The aim of this study was to examine whether MAA adducts might participate in the immune response associated with human alcohol-induced liver disease. Circulating antibodies against MAA adducts were evaluated in 50 patients with alcohol-induced hepatitis or cirrhosis, in 40 patients with non-alcohol-induced liver disease, in 15 heavy drinkers without liver damage and in 40 healthy controls by enzyme-linked immunosorbent assays (ELISA). Immunoglobulin G (IgG) reacting with MAA-modified proteins were significantly increased in the patients with alcohol-induced cirrhosis or hepatitis. The individual levels of anti-MAA IgG in those patients were associated with the severity of liver damage. Anti-MAA antibodies were also positively correlated with the levels of IgG recognizing epitopes generated by acetaldehyde and malonildialdehyde. However, competitive inhibition experiments indicated that the anti-MAA antibodies were unrelated to those against acetaldehyde-or malonildialdehydederived antigens and mainly recognized a specific, cyclic MAA epitope. Some degree of immune reactivity towards MAA adducts was also observed in patients with nonalcohol-induced liver injury. However, competitive ELISA showed that the antigens recognized by these sera were not the cyclic MAA adducts. Altogether, these results showed the formation of MAA antigens during alcohol-induced liver disease and suggest their possible contribution to the development of immunologic reactions associated with alcohol-related liver damage. (HEPATOLOGY 2000;31:878-884.)

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Alcohol and Breast Cancer

Singletary¹,

Gapstur²

2001

JAMA

395

120

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The association of alcohol consumption with increased risk for breast cancer has been a consistent finding in a majority of epidemiologic studies during the past 2 decades. Herein, we summarize information on this association from human and animal investigations, with particular reference to epidemiologic data published since 1995. increased estrogen and androgen levels in women consuming alcohol appear to be important mechanisms underlying the association. Other plausible mechanisms include enhanced mammary gland susceptibility to carcinogenesis, increased mammary carcinogen dna damage, and greater metastatic potential of breast cancer cells, processes for which the magnitude likely depends on the amount of alcohol consumed. Susceptibility to the breast cancer-enhancing effect of alcohol may also be affected by other dietary factors (such as low folate intake), lifestyle habits (such as use of hormone replacement therapy), or biological characteristics (such as tumor hormone receptor status). Additional progress in understanding alcohol's enhancing effect on breast cancer will depend on a better understanding of the interactions between alcohol and other risk factors and on additional insights into the multiple biological mechanisms involved.

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Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration

Cited by 224 publications

References 6 publications

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease

Alcohol and Breast Cancer

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