Formation of a vitamin C conjugate of acrolein and its paraoxonase-mediated conversion into 5,6,7,8-tetrahydroxy-4-oxooctanal.

Vitamin C (ascorbic acid) has been reported to participate in Michael addition reactions in vitro to form vitamin C conjugates with alpha,beta-unsaturated aldehydes, such as acrolein. This study shows evidence for the formation and metabolism of the vitamin C conjugate of acrolein (AscACR) in cultured human monocytic THP-1 cells exposed to acrolein diacetate. By using (18)O and (13)C labeling in combination with liquid chromatography-tandem mass spectrometry, AscACR was shown to undergo hydrolytic conversion of the ascorbyl lactone into an intermediate carboxylic acid. Subsequent decarboxylation of the carboxylic acid yielded 5,6,7,8-tetrahydroxy-4-oxooctanal (THO). When THP-1 cells were pretreated with ascorbic acid (1 mM, 18 h) and then exposed to acrolein diacetate, THO was detected as its pentafluorobenzyl oxime derivative in the cell lysates and medium. Treatment of THP-1 cells with both ascorbic acid and acrolein diacetate was required for THO formation. The formation of THO from AscACR was facilitated by the lactonase enzymes, human recombinant paraoxonases 1 and 2. THP-1 cells exhibited PON activity, which explains the catalytic conversion of AscACR into THO in these cells. THO was formed in addition to metabolites of the glutathione conjugate of acrolein, indicating that THO formation contributes to the elimination of acrolein in a cellular environment.

[1]  J. Stevens,et al.  Covalent interaction of ascorbic acid with natural products. , 2009, Phytochemistry.

[2]  Heather C. Kuiper,et al.  Ascorbic acid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells. , 2009, Chemical research in toxicology.

[3]  G. Rimbach,et al.  Ascorbigen: chemistry, occurrence, and biologic properties. , 2009, Clinics in dermatology.

[4]  B. Frei,et al.  Vitamin C and cancer revisited , 2008, Proceedings of the National Academy of Sciences.

[5]  M. Aviram,et al.  Characterization of the PON1 active site using modeling simulation, in relation to PON1 lactonase activity. , 2008, Bioorganic & medicinal chemistry.

[6]  K. Jonscher,et al.  Acrolein Inhibits Cytokine Gene Expression by Alkylating Cysteine and Arginine Residues in the NF-κB1 DNA Binding Domain* , 2007, Journal of Biological Chemistry.

[7]  D. Hatsukami,et al.  Quantitation of acrolein-derived (3-hydroxypropyl)mercapturic acid in human urine by liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: effects of cigarette smoking. , 2007, Chemical research in toxicology.

[8]  M. Tang,et al.  Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair , 2006, Proceedings of the National Academy of Sciences.

[9]  K. Croft,et al.  Augmentation of monocyte intracellular ascorbate in vitro protects cells from oxidative damage and inflammatory responses. , 2006, Biochemical and biophysical research communications.

[10]  E. Greenberg,et al.  Human and murine paraoxonase 1 are host modulators of Pseudomonas aeruginosa quorum-sensing. , 2005, FEMS microbiology letters.

[11]  James B. Mitchell,et al.  Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Shi,et al.  Glutathione and Ascorbic Acid Enhance Recovery of Guinea Pig Spinal Cord White Matter Following Ischemia and Acrolein Exposure , 2005, Pathobiology.

[13]  R. Sunahara,et al.  Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificitiess⃞s⃞ The online version of this article (available at http://www.jlr.org) contains additional text, figures, and references. Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M , 2005, Journal of Lipid Research.

[14]  Olga Khersonsky,et al.  Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase. , 2005, Biochemistry.

[15]  Kazuyuki Nakamura,et al.  Effect of Ascorbate on Acrolein Modification of Very Low Density Lipoprotein and Uptake of Oxidized Apolipoprotein E by Hepatocytes , 2005, Bioscience, biotechnology, and biochemistry.

[16]  M. Aviram,et al.  Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. , 2004, Free radical biology & medicine.

[17]  M. Aviram,et al.  Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. , 2004, Free radical biology & medicine.

[18]  M. Utz.  NMR Spectroscopy in the Solid State , 2003 .

[19]  C. Watson,et al.  Mouse Macrophage Paraoxonase 2 Activity Is Increased Whereas Cellular Paraoxonase 3 Activity Is Decreased Under Oxidative Stress , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[20]  L. Klotz,et al.  Identification of Cytosolic Leucyl Aminopeptidase (EC 3.4.11.1) as the Major Cysteinylglycine-Hydrolysing Activity in Rat Liver , 2003, Biological chemistry.

[21]  C. Cross,et al.  Acrolein-induced cytotoxicity in cultured human bronchial epithelial cells. Modulation by alpha-tocopherol and ascorbic acid. , 2002, Toxicology.

[22]  M. Preobrazhenskaya,et al.  Transformations of ascorbigen in vivo into ascorbigen acid and 1-deoxy-1-(indol-3-yl)ketoses , 2000 .

[23]  P. Stetson,et al.  Rabbit Serum Paraoxonase 3 (PON3) Is a High Density Lipoprotein-associated Lactonase and Protects Low Density Lipoprotein against Oxidation* , 2000, The Journal of Biological Chemistry.

[24]  F. Q. Schafer,et al.  Free radicals, oxidants, and antioxidants. , 2000, Teratology.

[25]  A. Fathi,et al.  Michael adducts of ascorbic acid as inhibitors of protein phosphatase 2A and inducers of apoptosis. , 2000, Bioorganic & medicinal chemistry letters.

[26]  M. Preobrazhenskaya,et al.  Transformation of ascorbigen into 1-deoxy-1-(indol-3-yl)-α-L-sorbopyranose and 1-deoxy-1-(indol-3-yl)-α-L-tagatopyranose , 1996 .

[27]  C. Harris,et al.  Mutagens from heated Chinese and U.S. cooking oils. , 1995, Journal of the National Cancer Institute.

[28]  K. Albert,et al.  Formation of heterocyclic products in michael reactions of ascorbic acid with α,β-unsaturated compounds. 3rd communication . Structural analysis of michael adducts of ascorbic acid by 13C-nmr spectroscopy in the solid state †‡ , 1992 .

[29]  Sareen S. Gropper,et al.  Advanced Nutrition and Human Metabolism , 1990 .

[30]  P. Bergsten,et al.  Millimolar concentrations of ascorbic acid in purified human mononuclear leukocytes. Depletion and reaccumulation. , 1990, The Journal of biological chemistry.

[31]  K. Eger,et al.  Heterocyclizations of Ascorbic Acids with α,β-Unsaturated Aldehydes and Ketones. Part 2. Michael Reactions of Ascorbic Acids with Acrolein Derivatives. Structural and Physicochemical Behaviour. , 1989 .

[32]  C. George,et al.  New Furo(3,2-b)furans Derived from L-Ascorbic Acid. , 1989 .

[33]  G. Folkers,et al.  Unexpected Formation of a Heterocyclic Spiran in the Michael Reaction of Ascorbic Acid with Acrolein. , 1987 .

[34]  J. Flippen-Anderson,et al.  Stereospecificity of a New Reaction of L-Ascorbic Acid with cis and trans Olefinic 1,4-Dicarbonyl Compounds. , 1987 .

[35]  M. Baseler,et al.  A new class of synthetic biological response modifiers: the methylfurylbutyrolactones (Nafocare B). , 1986, Journal of biological response modifiers.

[36]  S. Hecht,et al.  Formation of cyclic 1,N2-propanodeoxyguanosine adducts in DNA upon reaction with acrolein or crotonaldehyde. , 1984, Cancer research.

[37]  C. Kaye.  Biosynthesis of mercapturic acids from allyl alcohol, allyl esters and acrolein. , 1973, The Biochemical journal.

[38]  M. Kutáček,et al.  Biogenesis of Ascorbigen, 3-Indolylacetonitrile and Indole-3-carboxylic Acid from D,L-Tryptophan-3-14C in Brassica oleracea L. , 1960, Nature.

[39]  J. F. Stevens,et al.  Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease. , 2008, Molecular nutrition & food research.

[40]  K. Kraemer,et al.  Vitamin C: an introduction. , 2002 .

[41]  A. Sepulveda,et al.  γ-Glutamyl transpeptidase: What does the organization and expression of a multipromoter gene tell us about its functions? , 1995 .

[42]  J. Flippen-Anderson,et al.  A new role for l-ascorbic acid: michael donor to α,β-unsaturated carbonyl compounds , 1983 .