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Mechanism of DNA Damage and Apoptosis Induced by Tetrahydropapaveroline, a Metabolite of Dopamine

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Abstract

Tetrahydropapaveroline (THP), a metabolite of dopamine, has been suspected to be associated with dopaminergic neurotoxicity of L-DOPA. THP induced apoptosis in human leukemia cell line HL-60 cells, but did not in its hydrogen peroxide (H2O2)-resistant clone HP100. THP-induced DNA ladder formation in HL-60 cells was inhibited by a metal chelator. THP induced damage to 32P-labeled DNA fragments in the presence of metals. In the presence of Fe(III)EDTA, THP caused DNA damage at every nucleotide. The DNA damage was inhibited by free hydroxy radical (·OH) scavengers and catalase, suggesting that the Fe(III)EDTA-mediated DNA damage is mainly due to ·OH generation. In the presence of Cu(II), THP caused DNA damage mainly at T and G of 5′-TG-3′ sequence. The inhibitive effect of catalase and bathocuproine on Cu(II)-mediated DNA damage suggested that H2O2 and Cu(I) participate in the DNA damage. This study demonstrated that THP-induced apoptosis via reactive oxygen species generated from reaction of H2O2 and metals plays an important role in cytotoxicity of L-DOPA.

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Abbreviations

THP:

tetrahydropapaveroline

PD:

Parkinson’s disease

H2O2 :

hydrogen peroxide

DA:

dopamine

MAO:

monoamine oxidase

8-oxodG:

8-oxo-7,8-dihydro-2′-deoxyguanosine

CIP:

calf intestine phosphatase

DTPA:

diethylenetriamine-N,N,N′,N′′,N′′-pentaacetic acid

DMSO:

dimethylsulfoxide

SOD:

superoxide dismutase

Fpg:

formamidopyrimidine-DNA glycosylase

HPLC-ECD:

an electrochemical detector coupled to high-performance liquid chromatography

References

  1. Basma AN, Morris EJ, Nicklas WJ, Geller HM (1995) L-dopa cytotoxicity to PC12 cells in culture is via its auto-oxidation. J Neurochem 64:825–832

    Article  PubMed  CAS  Google Scholar 

  2. Walkinshaw G, Waters CM (1995) Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson’s disease. J Clin Invest 95:2458–2464

    Article  PubMed  CAS  Google Scholar 

  3. Zou L, Jankovic J, Rowe DB, Xie W, Appel SH, Le W (1999) Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity. Life Sci 64:1275–1285

    Article  PubMed  CAS  Google Scholar 

  4. Clement MV, Long LH, Ramalingam J, Halliwell B (2002) The cytotoxicity of dopamine may be an artefact of cell culture. J Neurochem 81:414–421

    Article  PubMed  CAS  Google Scholar 

  5. Liu WG, Chen Y, Li B, Lu GQ, Chen SD (2004) Neuroprotection by pergolide against levodopa-induced cytotoxicity of neural stem cells. Neurochem Res 29:2207–2214

    Article  PubMed  CAS  Google Scholar 

  6. Yin SY, Lee JJ, Kim YM, Jin CM, Yang YJ, Kang MH, Kai M, Lee MK (2004) Effects of (1R,9S)-beta-hydrastine on l-DOPA-induced cytotoxicity in PC12 cells. Eur J Pharmacol 488:71–77

    Article  PubMed  CAS  Google Scholar 

  7. Sandler M, Carter SB, Hunter KR, Stern GM (1973) Tetrahydroisoquinoline alkaloids: in vivo metabolites of L-dopa in man. Nature 241:439–443

    Article  PubMed  CAS  Google Scholar 

  8. Matsubara K, Fukushima S, Akane A, Kobayashi S, Shiono H (1992) Increased urinary morphine, codeine and tetrahydropapaveroline in parkinsonian patient undergoing l-3,4-dihydroxyphenylalanine therapy: a possible biosynthetic pathway of morphine from L-3,4-dihydroxyphenylalanine in humans. J Pharmacol Exp Ther 260:974–978

    PubMed  CAS  Google Scholar 

  9. Cashaw JL (1993) Determination of tetrahydropapaveroline in the urine of parkinsonian patients receiving L-dopa-carbidopa (Sinemet) therapy by high-performance liquid chromatography. J Chromatogr 613:267–273

    Article  PubMed  CAS  Google Scholar 

  10. Turner AJ, Baker KM, Algeri S, Erigerio A, Garattini S (1974) Tetrahydropapaveroline: formation in vivo and in vitro in rat brain. Life Sci 14:2247–2257

    Article  PubMed  CAS  Google Scholar 

  11. Maruyama W, Sango K, Iwasa K, Minami C, Dostert P, Kawai M, Moriyasu M, Naoi M (2000) Dopaminergic neurotoxins, 6,7-dihydroxy-1-(3′, 4′-dihydroxybenzyl)-isoquinolines, cause different types of cell death in SH-SY5Y cells: apoptosis was induced by oxidized papaverolines and necrosis by reduced tetrahydropapaverolines. Neurosci Lett 291:89–92

    Article  PubMed  CAS  Google Scholar 

  12. Shin MH, Jang JH, Surh YJ (2004) Potential roles of NF-kappaB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline. Free Radic Biol Med 36:1185–1194

    Article  PubMed  CAS  Google Scholar 

  13. Soh Y, Shin MH, Lee JS, Jang JH, Kim OH, Kang H, Surh YJ (2003) Oxidative DNA damage and glioma cell death induced by tetrahydropapaveroline. Mutat Res 544:129–142

    Article  PubMed  CAS  Google Scholar 

  14. Suzuki K, Mizuno Y, Yoshida M (1990) Inhibition of mitochondrial respiration by 1,2,3,4-tetrahydroisoquinoline-like endogenous alkaloids in mouse brain. Neurochem Res 15:705–710

    Article  PubMed  CAS  Google Scholar 

  15. Oikawa S, Nishino K, Inoue S, Mizutani T, Kawanishi S (1998) Oxidative DNA damage and apoptosis induced by metabolites of butylated hydroxytoluene. Biochem Pharmacol 56:361–370

    Article  PubMed  CAS  Google Scholar 

  16. Oikawa S, Murakami K, Kawanishi S (2003) Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. Oncogene 22:3530–3538

    Article  PubMed  CAS  Google Scholar 

  17. Kobayashi H, Oikawa S, Hirakawa K, Kawanishi S (2004) Metal-mediated oxidative damage to cellular and isolated DNA by gallic acid, a metabolite of antioxidant propyl gallate. Mutat Res 558:111–120

    PubMed  CAS  Google Scholar 

  18. Maxam AM, Gilbert W (1980) Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol 65:499–560

    Article  PubMed  CAS  Google Scholar 

  19. Kasai H, Crain PF, Kuchino Y, Nishimura S, Ootsuyama A, Tanooka H (1986) Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis 7:1849–1851

    Article  PubMed  CAS  Google Scholar 

  20. Ito K, Inoue S, Yamamoto K, Kawanishi S (1993) 8-Hydroxydeoxyguanosine formation at the 5′ site of 5′-GG-3′ sequences in double-stranded DNA by UV radiation with riboflavin. J Biol Chem 268:13221–13227

    PubMed  CAS  Google Scholar 

  21. Rao PS, Luber JM, Jr. Milinowicz J, Lalezari P, Mueller HS (1988) Specificity of oxygen radical scavengers and assessment of free radical scavenger efficiency using luminol enhanced chemiluminescence. Biochem Biophys Res Commun 150:39–44

    Article  PubMed  CAS  Google Scholar 

  22. Spassky A, Angelov D (1997) Influence of the local helical conformation on the guanine modifications generated from one-electron DNA oxidation. Biochemistry 36:6571–6576

    Article  PubMed  CAS  Google Scholar 

  23. Kasugai I, Yamada M (1992) High production of catalase in hydrogen peroxide-resistant human leukemia HL-60 cell lines. Leuk Res 16:173–179

    Article  PubMed  CAS  Google Scholar 

  24. Hertzberg RP, Dervan PB (1984) Cleavage of DNA with methidiumpropyl-EDTA-iron(II): reaction conditions and product analyses Biochemistry. 23:3934–3945

    Article  PubMed  CAS  Google Scholar 

  25. Kawanishi S, Inoue S, Sano S (1986) Mechanism of DNA cleavage induced by sodium chromate(VI) in the presence of hydrogen peroxide. J Biol Chem 261:5952–5958

    PubMed  CAS  Google Scholar 

  26. Inoue S, Kawanishi S (1987) Hydroxyl radical production and human DNA damage induced by ferric nitrilotriacetate and hydrogen peroxide. Cancer Res 47:6522–6527

    PubMed  CAS  Google Scholar 

  27. Celander DW, Cech TR (1990) Iron(II)-ethylenediaminetetraacetic acid catalyzed cleavage of RNA and DNA oligonucleotides: similar reactivity toward single- and double-stranded forms. Biochemistry 29:1355–1361

    Article  PubMed  CAS  Google Scholar 

  28. Boiteux S, Gajewski E, Laval J, Dizdaroglu M (1992) Substrate specificity of the Escherichia coli Fpg protein (formamidopyrimidine-DNA glycosylase): excision of purine lesions in DNA produced by ionizing radiation or photosensitization. Biochemistry 31:106–110

    Article  PubMed  CAS  Google Scholar 

  29. Bruner SD, Norman DP, Verdine GL (2000) Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403:859–866

    Article  PubMed  CAS  Google Scholar 

  30. David-Cordonnier MH, Laval J, O’Neill P (2000) Clustered DNA damage, influence on damage excision by XRS5 nuclear extracts and Escherichia coli Nth and Fpg proteins. J Biol Chem 275:11865–11873

    Article  PubMed  CAS  Google Scholar 

  31. Box HC, Dawidzik JB, Budzinski EE (2001) Free radical-induced double lesions in DNA. Free Radic Biol Med 31:856–868

    Article  PubMed  CAS  Google Scholar 

  32. Ohnishi S, Kawanishi S (2002) Double base lesions of DNA by a metabolite of carcinogenic benzo[a]pyrene. Biochem Biophys Res Commun 290:778–782

    Article  PubMed  CAS  Google Scholar 

  33. Blaisdell JO, Wallace SS (2001) Abortive base-excision repair of radiation-induced clustered DNA lesions in Escherichia coli. Proc Natl Acad Sci USA 98:7426–7430

    Article  PubMed  CAS  Google Scholar 

  34. Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F (2004) Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 19:997–1005

    Article  PubMed  Google Scholar 

  35. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow CW, Tanner C, Marek K (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351:2498–2508

    Article  PubMed  CAS  Google Scholar 

  36. Leveugle B, Faucheux BA, Bouras C, Nillesse N, Spik G, Hirsch EC, Agid Y, Hof PR (1996) Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases. Acta Neuropathol (Berl) 91:566–572

    Article  CAS  Google Scholar 

  37. Ke Y, Ming Qian Z (2003) Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol 2:246–253

    Article  PubMed  CAS  Google Scholar 

  38. Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, Giaveri G, Arosio P, Santambrogio P, Fariello RG, Karatekin E, Kleinman MH, Turro N, Hornykiewicz O, Zucca FA (2004) The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA 101:9843–9848

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan.

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Authors and Affiliations

  1. Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 514-8507, Mie, Japan

    Hatasu Kobayashi, Shinji Oikawa & Shosuke Kawanishi

  2. Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu, 514-8507, Mie, Japan

    Shinji Oikawa

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  1. Hatasu Kobayashi
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  2. Shinji Oikawa
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Correspondence to Shinji Oikawa.

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Kobayashi, H., Oikawa, S. & Kawanishi, S. Mechanism of DNA Damage and Apoptosis Induced by Tetrahydropapaveroline, a Metabolite of Dopamine. Neurochem Res 31, 523–532 (2006). https://doi.org/10.1007/s11064-006-9044-8

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