The Hepatocellular Metabolism of 4-Hydroxynonenal by Alcohol Dehydrogenase, Aldehyde Dehydrogenase, and Glutathione S-Transferase

Hartley, Dylan P.; Ruth, James A.; Petersen, Dennis R.

doi:10.1006/abbi.1995.1028

Cited by 239 publications

(176 citation statements)

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“…48,49 Therefore, inhibition of ALDH2 may cause accumulation of toxic acetaldehyde and lipid aldehyde such as the 4-hydroxynonenal produced after exposure to alcohol and other toxic compounds. 50 Likewise, inhibition of ATP synthase leads to reduced levels of ATP, 43 which may shift cell death mechanisms to necrosis from apoptosis, which requires ATP as an energy source.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of oxidized and S -nitrosylated mitochondrial proteins in alcoholic fatty liver of rats

et al. 2006

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Increased oxidative/nitrosative stress is a major contributing factor to alcohol-mediated mitochondrial dysfunction. However, which mitochondrial proteins are oxidatively modified under alcohol-induced oxidative/nitrosative stress is poorly understood. The aim of this study was to systematically investigate oxidized and/or S-nitrosylated mitochondrial proteins and to use a biotin-N-maleimide probe to evaluate their inactivation in alcoholic fatty livers of rats. Binge or chronic alcohol exposure significantly elevated nitric oxide, inducible nitric oxide synthase, and ethanol-inducible CYP2E1. The biotin-N-maleimide-labeled oxidized and/or S-nitrosylated mitochondrial proteins from pair-fed controls or alcohol-fed rat livers were subsequently purified with streptavidin-agarose. The overall patterns of oxidized and/or S-nitrosylated proteins resolved by 2-dimensional polyacrylamide gel electrophoresis were very similar in the chronic and binge alcohol treatment groups. Seventy-nine proteins that displayed differential spot intensities from those of control rats were identified by mass spectrometry. These include mitochondrial aldehyde dehydrogenase 2 (ALDH2), ATP synthase, acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, and many proteins involved in chaperone activity, mitochondrial electron transfer, and ion transport. The activity of 3-ketoacyl-CoA thiolase involved in mitochondrial ␤-oxidation of fatty acids was significantly inhibited in alcohol-exposed rat livers, consistent with hepatic fat accumulation, as determined by biochemical and histological analyses. Measurement of activity and immunoblot results showed that ALDH2 and ATP synthase were also inhibited through oxidative modification of their cysteine or tyrosine residues in alcoholic fatty livers of rats. In conclusion, our results help to explain the underlying mechanism for mitochondrial dysfunction and increased susceptibility to alcohol-mediated liver damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Section: Discussionmentioning

confidence: 99%

Inactivation of oxidized and S -nitrosylated mitochondrial proteins in alcoholic fatty liver of rats

et al. 2006

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“…Whereas most of these aldehydic products are produced in very low concentration, 2 ␣-␤-unsaturated aldehydes, malondialdehyde, and 4-hydroxy-2,3-nonenal (4-HNE) are produced in relatively large quantities and therefore are classified as major products of lipid peroxidation. 14 4-HNE elimination by conjugation with GSH, catalyzed by GST, represents 50% to 60% of the total 4-HNE removal by hepatocytes; other pathways responsible for 4-HNE metabolism are alcohol/aldehyde dehydrogenases. 14,15 Both, alpha [16][17][18][19] and microsomal 25 GST are able to metabolize 4-HNE.…”

Section: Discussionmentioning

confidence: 99%

“…13 GST-mediated conjugation of 4-HNE to GSH is the major pathway for 4-HNE metabolism. 14,15 Among the numerous cytosolic GST isozymes, the alpha-class displays the highest activity toward lipid hydroperoxides and has been implicated in the protection against oxidative stress. [16][17][18][19] The microsomal GST, different from the cytosolic family, comprise a family of small (16-to 18-kd), membrane-associated proteins that have been shown to be active as a trimer of identical subunits [20][21][22] ; its activity can be increased by treatment with N-ethylmaleimide and other sulphydryl reagents, heat, oxidative stress, and protein dimerization.…”

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confidence: 99%

Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress

2001

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Induction of cytochrome P450 2E1 (CYP2E1) and the formation of reactive oxygen species (ROS) appear to be one of the mechanisms by which ethanol is hepatotoxic. Glutathione peroxidase and catalase detoxify H 2 O 2 . Glutathione Stransferases (GST) provide protection from membrane lipid peroxidation, have GSH peroxidase activity, and reduce lipid hydroperoxides. Previous studies showed an up-regulation of GSH synthesis in CYP2E1 expressing HepG2 cells; this finding prompted an evaluation of the levels of other antioxidant exzymes. In CYP2E1 expressing cells, the alpha and microsomal GST messenger RNA (mRNA) are increased by 4-and 2-fold, respectively, and catalase protein and mRNA is increased by 2-fold. The increase in alpha and microsomal GST mRNA correlates with increased total enzymatic activity and is caused by increased transcription as evidenced by run-on transcription assays. In HepG2 cells transfected to express a different cytochrome P450, CYP3A4, there was an increase in alpha GST. However, in contrast to the CYP2E1 expressing cells, neither microsomal GST nor catalase were induced, suggesting some specificity for CYP2E1. In agreement with an increased antioxidant defense system, the sensitivity to added prooxidants such as menadione, antimycin A, H 2 O 2 , and 4-hydroxynonenal was lower in the CYP2E1 expressing cells as compared with control cells. In conclusion, overexpression of CYP2E1 in HepG2 cells, besides elevating total GSH levels, also induces expression of catalase and alpha and microsomal GST. This induction confers resistance to the cells against several prooxidants and is suggested to reflect an adaptive response by the cells against CYP2E1-mediated oxidative stress. (HEPATOLOGY 2001;33:652-661.)The glutathione S-transferases (GST; EC 2.5.1.18) are a family of enzymes that catalyze the conjugation of glutathione (GSH) to a wide variety of hydrophobic molecules of both exogenous and endogenous origin. 1-3 The cytosolic GSTs are dimeric proteins of subunits having a molecular mass in the 22-to 28-kd range. On the basis of their amino acid sequence, 5 classes have been described, namely alpha, mu, pi, theta, and sigma. [4][5][6] In humans the alpha class, subunits A1 and A2, is the predominant GST accounting for about 85% of the total GST protein. The major GST subunits expressed in rat liver are the alpha class, subunits A1 and A2, and the mu class, subunits 3 and 4, 7,8 whereas most of the cytosolic GST in HepG2 cells is the alpha isozyme. 9 ␣,␤, unsaturated aldehydes, such as 4-hydroxy-2,3-nonenal (4-HNE) and other endogenous or exogenous aldehydes, are generated in response to a variety of oxidative stimuli such as free intracellular iron, 10 chronic ethanol consumption, 11,12 and treatment with anticancer drugs. 13 GST-mediated conjugation of 4-HNE to GSH is the major pathway for 4-HNE metabolism. 14,15 Among the numerous cytosolic GST isozymes, the alpha-class displays the highest activity toward lipid hydroperoxides and has been implicated in the protection against oxidative stress. [1...

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“…Mammalian alcohol dehydrogenase (ADH) represents a system of related enzymes, of which presently six classes are distinguished [1], capable of reducing a wide array of aldehydes [2~], and is, together with aldehyde dehydrogenase, aldehyde reductase and glutathione S-transferase, one of the major aldehyde-metabolising enzymes [4]. The major organ for aldehyde detoxification in humans is the liver where three main classes of ADH have been characterised, classes I-III [5], and class I is further divided into isozymes derived from the presence of three subunit types (c~, [3, y) [6].…”

Section: Introductionmentioning

confidence: 99%

Aldehyde dismutase activity of human liver alcohol dehydrogenase

et al. 1996

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Human alcohol dehydrogenases of class I and class II but not class III catalyse NAD+-dependent aldehyde oxidation in addition to the NADH-dependent aldehyde reduction. The two reactions are coupled, i.e. the enzymes display dismutase activity. Dismutase activity of recombinantly expressed human class I isozymes [~1[~1 and T2T2, class II and class III alcohol dehydrogenases was assayed with butanal as snbstrate by gas chromatographic-mass spectrometric quantitations of butanol and butyric acid. The class I Y2Y2 isozyme showed a pronounced dismutase activity with a high kcat, 1300 min -1, and a moderate Km, 1.2 mM. The class I ~1111 isozyme and the class II alcohol dehydrogenase showed moderate catalytic efficiencies for dismutase activity with lower kcat values, 60-75 min -1. 4-Methylpyrazole, a potent class I ADH inhibitor, inhibited the class I dismutation completely, but cyanamide, an inhibitor of mitochondrial aldehyde dehydrogenase, did not affect the dismutation. The dismutase reaction might be important for metabolism of aldehydes during inhibition or lack of mitochondrial aldehyde dehydrogenase activity.

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The Hepatocellular Metabolism of 4-Hydroxynonenal by Alcohol Dehydrogenase, Aldehyde Dehydrogenase, and Glutathione S-Transferase

Cited by 239 publications

References 0 publications

Inactivation of oxidized and S -nitrosylated mitochondrial proteins in alcoholic fatty liver of rats

Inactivation of oxidized and S -nitrosylated mitochondrial proteins in alcoholic fatty liver of rats

Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress

Aldehyde dismutase activity of human liver alcohol dehydrogenase

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