Cancer and Metastasis Reviews

, Volume 13, Issue 3–4, pp 303–308 | Cite as

Generation of mutagens during arachidonic acid metabolism

  • Lawrence J. Marnett

Key words

arachidonic acid mutagens tumors PGH synthase MDA 


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  1. 1.
    Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61: 759–767, 1990Google Scholar
  2. 2.
    Marnett LJ: Polycyclic aromatic hydrocarbon oxidation during prostaglandin biosynthesis. Life Sci 29: 531–546, 1981Google Scholar
  3. 3.
    Marnett LJ, Eling TE: Cooxidation during prostaglandin biosynthesis: A pathway for the metabolic activation of xenobiotics. In: Hodgson E, Bend JR, Philpot RM (eds) Reviews in biochemical toxicology. Elsevier/North Holland, 1983, pp 135–172Google Scholar
  4. 4.
    Marnett LJ (ed.) Arachidonic Acid Metabolism and Tumor Initiation. Martinus Nijhoff PUblishing, Boston, 1985Google Scholar
  5. 5.
    Smith BJ, Curtis JF, Eling TE: Bioactivation of xenobiotics by prostaglandin H synthase. Chem Biol Interact 79: 245–264, 1991Google Scholar
  6. 6.
    Marnett LJ, Reed GA, Dennison DJ: Prostaglandin synthetase dependent activation of 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene to mutagenic derivatives. Biochem Biophys Res Commun 82: 210–216, 1978Google Scholar
  7. 7.
    Robertson IGC, Sivarajah K, Eling TE, Zeiger E: Activation of some aromatic amines to mutagenic products by prostaglandin endoperoxide synthetase. Cancer Res 43: 476–480, 1983Google Scholar
  8. 8.
    Sarkar FH, Radcliff G, Callewaert DM, Marnett LJ, Eling T, Daston DS, Caspary WJ: Mutagenic response of mouse lymphoma cells after activation of benzidine and 2-aminofluorene with purified prostaglandin H synthase. Mutat Res 242: 319–328, 1990Google Scholar
  9. 9.
    Sarkar FH, Radcliff G, Callewaert DM: Purified prostaglandin synthase activates aromatic amines to derivatives that are mutagenic toSalmonella typhimurium. Mutat Res Lett 282: 273–281, 1992Google Scholar
  10. 10.
    Degan GH: Prostaglandin-H synthase containing cell lines as tools for studying metabolism and toxicity of xenobiotics. Toxicology 82: 243–256, 1993Google Scholar
  11. 11.
    Murasaki G, Zenser TV, Davis BB, Cohen SM: Inhibition by aspirin of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced bladder carcinogenesis and enhancement of forestomach carcinogenesis. Carcinogenesis 5: 53–55, 1984Google Scholar
  12. 12.
    Zenser TV, Palmier MO, Mattammal MB, Bolla RI, Davis BB: Comparative effects of prostaglandin H synthase-catalyzed binding of two 5-nitrofuran urinary bladder carcinogens. J Pharmacol Exp Ther 227: 139–143, 1983Google Scholar
  13. 13.
    Smith RD, Kehrer JP: Cooxidation of cyclophosphamide as an alternative pathway for its bioactivation and lung toxicity. Cancer Res 51: 542–548, 1991Google Scholar
  14. 14.
    Kubow S, Wells PG:In vitro bioactivation ofphenytoin to a reactive free radical intermediate by prostaglandin synthetase, horseradish peroxidase, and thyroid peroxidase. Mol Pharmacol 35: 504–511, 1989Google Scholar
  15. 15.
    Rice JR, Zenser TV, Davis BB: Prostaglandin synthase-dependent cooxidation and aromatic amine carcinogenesis. In: Marnett LJ (ed.) Arachidonic acid metabolism and tumor initiation. Martinus Nijhoff, 1985, pp 125–169Google Scholar
  16. 16.
    Flammang TJ, Yamazoe Y, Benson RW, Roberts DW, Potter DW, Chu DZJ, Lang NP, Kadlubar FF: Arachidonic aciddependent peroxidative activation of carcinogenic arylamines by extrahepatic human tissue microsomes. Cancer Res 49: 1977–1982, 1989Google Scholar
  17. 17.
    Lambeir AM, Markey CM, Dunford HB, Marnett LJ: Spectral properties of the higher oxidation states of prostaglandin H synthase. J Biol Chem 260: 14894–14896, 1985Google Scholar
  18. 18.
    Dunford HB, Stillman JS: On the function and mechanism of action of peroxidases. Coord Chem Rev 19: 187–251, 1976Google Scholar
  19. 19.
    Hsuanyu Y, Dunford HB: Prostaglandin H synthase kinetics. The effect of substituted phenols on cyclooxygenase activity and the substituent effect on phenolic peroxidatic activity. J Biol Chem 267: 17649–17657, 1992Google Scholar
  20. 20.
    Guengerich FP, MacDonald TL: Mechanisms of cytochrome P-450 catalysis. FASEB J 4: 2453–2459, 1990Google Scholar
  21. 21.
    MacDonald TL, Gutheim WG, Martin RB, Guengerich FP: Oxidation of substituted N,N-dimethylanilines by cytochrome P-450: Estimation of the effective oxidation potential of cytochrome P-450. Biochemistry 28: 2071–2077, 1989Google Scholar
  22. 22.
    Picot D, Loll PJ, Garavito RM: The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367: 243–249, 1994Google Scholar
  23. 23.
    Wendel A: Glutathione peroxidase. In: Jakoby WB (ed.) Enzymatic basis of detoxication. Academic Press, New York, 1980, pp 333–353Google Scholar
  24. 24.
    Labeque R, Marnett LJ: Homolytic and heterolytic scission of organic hydroperoxides by meso-tetraphenylporphinatoiron (III) and its relation to olefin epoxidation. J Am Chem Soc 111: 6621–6627, 1989Google Scholar
  25. 25.
    Wilcox AL, Marnett LJ: Polyunsaturated fatty acid alkoxyl radicals exist as carbon-centered epoxyallylic radicals: A key step in hydroperoxide-amplified lipid peroxidation. Chem Res Toxicol 6: 413–416, 1993Google Scholar
  26. 26.
    Dix TA, Fontana R, Panthani A, Marnett LJ: Hematin-catalyzed epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) by polyunsaturated fatty acid hydroperoxides. J Biol Chem 260: 5358–5365, 1985Google Scholar
  27. 27.
    Eling TE, Thompson DC, Foureman GL, Curtis JF, Hughes MF: Prostaglandin H synthase and xenobiotic oxidation. Annu Rev Pharmacol Toxicol 30: 1–45, 1990Google Scholar
  28. 28.
    Ji C, Marnett LJ: Oxygen radical-dependent epoxidation of (7S,8S)-dihydroxy-7,8-dihydrobenzo[a]pyrene in mouse skinin vivo. Stimulation by phorbol esters and inhibition by antiinflammatory steroids. J Biol Chem 267: 17842–17848, 1992Google Scholar
  29. 29.
    Kensler TW, Egner TA, Moore KG, Taffe BG, Twerdok LE, Trush MA: Role of inflammatory cells in the metabolic activation of polycyclic aromatic hydrocarbons in mouse skin. Toxicol Appl Pharmacol 90: 337–346, 1987Google Scholar
  30. 30.
    Hamberg M, Samuelsson B: On the mechanism of the biosynthesis of prostaglandins E1 and F. J Biol Chem 242: 5336–5343, 1967Google Scholar
  31. 31.
    Diczfalusy U, Falardeau P, Hammarstrom S: Conversion of prostaglandin endoperoxides to C17-hydroxyacids by human platelet thromboxane synthase. FEBS Lett 84: 271–274, 1977Google Scholar
  32. 32.
    Mukai FH, Goldstein BD: Mutagenicity of malondialdehyde, a decomposition product of peroxidized polyunsaturated fatty acids. Science 191: 868–869, 1976Google Scholar
  33. 33.
    Basu AK, Marnett LJ: Unequivocal demonstration that malondialdehyde is a mutagen. Carcinogenesis 4: 331–333, 1983Google Scholar
  34. 34.
    Spalding JW: Toxicology and carcinogenesis studies of malondialdehyde sodium salt (3-hydroxy-2-propenal, sodium salt) in F344/N rats and B6C3F1 mice. NTP Technical Report 331: 5–13, 1988Google Scholar
  35. 35.
    Yau TM: Mutagenicity and cytotoxicity of malondialdehyde in mammalian cells. Mech Ageing Dev 11: 137–144, 1979Google Scholar
  36. 36.
    Bernheim F, Bernheim MLC, Wilbur KM: The reaction between thiobarbituric acid and the oxidation products of certain lipids. J Biol Chem 174: 257–264, 1948Google Scholar
  37. 37.
    Janero DR: Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radical Biol Med 9: 515–540, 1990Google Scholar
  38. 38.
    Seto H, Okuda T, Takesue T, Ikemura T: Reaction of malondialdehyde with nucleic acid. I. Formation of fluorescent pyrimido[1,2-a]purin-10(3H)-one nucleosides. Bull Chem Soc Jpn 56: 1799–1802, 1983Google Scholar
  39. 39.
    Nair V, Turner GA, Offerman RJ: Novel adducts from the modification of nucleic acid bases by malondialdehyde. J Am Chem Soc 106: 3370–3371, 1984Google Scholar
  40. 40.
    Marnett LJ, Basu AK, O'Hara SM, Weller PE, Rahman AFMM, Oliver JP: Reaction of malondialdehyde with guanine nucleosides: formation of adducts containing oxadiazabicyclononene residues in the base-pairing region. J Am Chem Soc 108: 1348–1350, 1986Google Scholar
  41. 41.
    Stone K, Ksebati M, Marnett LJ: Investigation of the adducts formed by reaction of malondialdehyde with adenosine. Chem Res Toxicol 3: 33–38, 1990Google Scholar
  42. 42.
    Stone K, Uzieblo A, Marnett LJ: Studies of the reaction of malondialdehyde with cytosine nucleosides. Chem Res Toxicol 3: 467–472, 1990Google Scholar
  43. 43.
    Basu AK, O'Hara SM, Valladier P, Stone K, Mols O, Marnett LJ: Identification of adducts formed by reaction of guanine nucleosides with malondialdehyde and structurally related aldehydes. Chem Res Toxicol 1: 53–59, 1988Google Scholar
  44. 44.
    Basu AK, Marnett LJ, Romano LJ: Dissociation of malondialdehyde mutagenicity inSalmonella typhimurium from its ability to induce interstrand DNA cross-links. Mutat Res 129: 39–46, 1984Google Scholar
  45. 45.
    Marnett LJ, Hurd HK, Hollstein MC, Levin DE, Esterbauer H, Ames BN: Naturally occurring carbonyl compounds are mutagens inSalmonella tester strain TA104. Mutat Res 148: 25–34, 1985Google Scholar
  46. 46.
    O'Hara SM, Marnett LJ: DNA sequence analysis of spontaneous and β-methoxy-acrolein-induced mutations inSalmonella typhimurium hisD3052. Mutat Res Fundam Mol Mech Mutagen 247: 45–56, 1991Google Scholar
  47. 47.
    Benamira M, Johnson K, Chaudhary A, Bruner K, Tibbetts C, Marnett LJ: The mutation spectrum of malondialdehyde. Carcinogenesis, in pressGoogle Scholar
  48. 48.
    Hollstein M, Sidransky D, Vogelestein B, Harris CC. p53 mutations in human cancer. Science 253: 49–53, 1991Google Scholar
  49. 49.
    Frederico LA, Kunkel TA, Shaw BR: A sensitive genetic assay for the detection of cytosine deamination: Determination of rate constants and the activation energy. Biochemistry 29: 2532–2537, 1990Google Scholar
  50. 50.
    Strauss BS: The ‘A rule’ of mutagen specificity: A consequence of DNA polymerase bypass of non-instructional lesions? BioEssays 13: 79–84, 1991Google Scholar
  51. 51.
    Grollman AP: Site specific mutagenesis. In: Mutations and the Environment. Wiley-Liss, New York, 1990, pp 61–70Google Scholar
  52. 52.
    Goda Y, Marnett LJ: High performance liquid chromatography with electrochemical detection for determination of the major malondialdehyde-guanine adduct. Chem Res Toxicol 4: 520–524, 1991Google Scholar
  53. 53.
    Vaca CE, Vodicka P, Hemminki K: Determination of malonaldehyde-modified 2′-deoxyguanosine-3′-monophosphate and DNA by32P-postlabelling. Carcinogenesis 13: 593–599, 1992Google Scholar
  54. 54.
    Chaudhary AK, Nokubo M, Marnett LJ, Blair IA: Analysis of the malondialdehyde-2′-deoxyguanosine adduct in rat liver DNA by gas chromatography/electron capture negative chemical ionization mass spectrometry. Biolog Mass Spectros 23: 457–464, 1994Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Lawrence J. Marnett
    • 1
    • 2
  1. 1.The Vanderbilt Cancer CenterA.B. Hancock Jr. Memorial Laboratory for Cancer ResearchVanderbiltUSA
  2. 2.Department of BiochemistryUniversity School of MedicineNashvilleUSA

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