Cytotoxicity of beta-carotene cleavage products and its prevention by antioxidants

• Autorzy: Alija A. J. , Bresgen N. , Bojaxhi E. , Vogl C. , Siems W. , Eckl P. M.
• Języki publikacji: EN

Abstrakty

EN

 When we investigated the genotoxicity of β-carotene cleavage products (CPs) in primary rat hepatocytes stimulated to proliferate, we observed dose-dependent increases of chromosomal aberrations, sister chromatid exchanges and micronuclei. In contrast to other genotoxic substances, however, this increased genotoxicity was not accompanied by increased cytotoxicity. As a consequence we observed metaphases showing massive chromosomal damage, indicating inhibition of apoptosis by CPs enabling these cells to proceed in the cell cycle. Since proliferative stimulation by growth factors may support this effect, the in vitro toxicological effects of CPs were studied on proliferatively quiescent primary rat hepatocytes. A significant increase of both apoptosis and necrosis was found. Supplementation with antioxidants did not significantly lower the level of apoptosis, while the level of necrosis was significantly reduced by Trolox and N-acetylcysteine at all concentrations tested as well as ascorbic acid (50 μM) and a combination of Trolox (50 μM) and ascorbic acid (50 μM). These observations indicate that a) the cytotoxic potential in combination with the genotoxic potential of CPs may promote the initiation of cells due to compensatory cell division in exposed tissues and may aggravate inflammatory processes under chronic exposure, and b) the applied antioxidants may protect from cytotoxicity primarily via the detoxification of aldehydic β-carotene cleavage products.

Słowa kluczowe

EN

cytotoxicity; beta-carotene; prevention; antioxidant; cleavage product; hepatocyte; apoptosis; necrosis; epidermal growth factor

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2010
• Tom: 57
• Numer: 2
• Opis fizyczny: p.217-221,fig.,ref.

Twórcy

autor

Alija A. J.

• Department of Biology, University of Prishtina, Prishtina, Kosovo

autor

Bresgen N.

autor

Bojaxhi E.

autor

Vogl C.

autor

Siems W.

autor

Eckl P. M.

Bibliografia

• Agarwal S, Rao AV (2000) Carotenoids and chronic diseases. Drug Metabol Drug Interact 17: 189-210. 
• Aidoo A, Lyn-Cook LE, Lensing S, Bishop ME, Wamer W (1995) In vivo antimutagenic activity of beta-carotene in rat spleen lymphocytes. Carcinogenesis 16: 2237-2241. 
• Alija AJ, Bresgen N, Sommerburg O, Siems W, Eckl PM (2004) Cytotoxic and genotoxic effects of beta-carotene breakdown products on primary rat hepatocytes. Carcinogenesis 25: 827-831.  
• Alija AJ, Bresgen N, Sommerburg O, Langhans CD, Siems W, Eckl PM (2006) Beta-carotene breakdown products enhance genotoxic effects of oxidative stress in primary rat hepatocytes. Carcinogenesis 27: 1128-1133.  
• Arriaga-Alba M, Rivera-Sanchez R, Parra-Cervantes G, Barro-Moreno F, Flores-Paz R, Garcia-Jimenez E (2000) Antimutagenesis of beta-carotene to mutations induced by quinolone on Salmonella typhimurium. Arch Med Res 31: 156-161. 
• Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA (2007) N-Acetylcysteine - a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 7: 355-359. 
• Blumberg J, Block G (1994) The alpha-tocopherol, beta-carotene cancer prevention study in finland. Nutr Rev 52: 242-245. 
• Bresgen N, Ohlenschläger I, Wacht N, Afazel S, Ladurner G, Eckl PM (2008) Ferritin and FasL (CD95L) mediate density dependent apoptosis in primary rat hepatocytes. J Cell Physiol 217: 800-808. 
• Dekhuijzen PN, van Beurden WJ (2006) The role for N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis 1: 99-106. 
• Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16: 663-669. 
• Ethier C, Raymond V-A, Musallam L, Houle R, Bilodeau M (2003) Antiapoptotic effect of EGF on mouse hepatocytes associated with downregulation of proapoptotic Bid protein. Am J Physiol Gastrointest Liver Physiol 285: G298-G308. 
• Fishbane S (2008) N-Acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol 3: 281-287. 
• Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R (1995) In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21: 1465-1468. 
• Hallfrisch J, Muller DC, Singh VN (1994) Vitamin A and E intakes and plasma concentrations of retinol, β-carotene and α-tocopherol in men and women of the Baltimore Longitudinal Study of Aging. Am J Clin Nutr 60: 176-182. 
• Halliwell B (2000) The antioxidant paradox. Lancet 355: 1179-1180. 
• Huerta S, Goulet EJ, Huerta-Ypez S, Livingston EH (2007) Screening and detection of apoptosis. J Surg Res 139: 143-156. 
• Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89: 31-41. 
• Laurora S, Tamagno E, Briatore F, Bardini P, Pizzimenti S, Toaldo C, Reffo P, Costelli P, Dianzani MU, Danni O, Barrera G (2005) 4-Hydroxynonenal modulation of p53 family gene expression in the SK-N-BE neuroblastoma cell line. Free Radic Biol Med 38: 215-225. 
• Li S, Chien S, Brånemark P-I (2005) Heat shock-induced necrosis and apoptosis in osteoblasts. J Orthopaed Res 6: 891-899.
• Liu C, Russell RM, Wang X-D (2004) α-Tocopherol and ascorbic acid decrease the production of β-apo-carotenals and increase the formation of retinoids from β-carotene in the lung tissues of cigarette smoke-exposed ferrets in vitro. J Nutr 134: 426-430. 
• Lu QY, Hung JC, Heber D, Go VL, Reuter VE, Cordon-Cardo C, Scher HI, Marshall JR, Zhang ZF (2001) Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Cancer Epidemiol Biomarkers Prev 10: 749-756. 
• Marques SA, Loureiro AP, Gomes OF, Garcia CC, DiMascio P, Medeiros MH (2004) Induction of 1,N(2)-etheno-2'-deoxyguanosine in DNA exposed to beta-carotene oxidation products. FEBS Lett 560: 125-130. 
• McClain DE, Kalinich JF, Ramakrishnan N (1995) Trolox inhibits apoptosis in irradiated MOLT-4 lymphocytes. FASEB J 9: 1345-1354. 
• Miranda CL, Reed RL, Kuiper HC, Alber S, Stevens JF (2009) Ascorbic acid promotes detoxification and elimination of 4-hydroxy-2(E)-nonenal in human monocytic THP-1 cells. Chem Res Toxicol 22: 863-874. 
• Michalopoulos G, Cianciulli HD, Novotny AR, Kligerman AD, Strom SC, Jirtle RL (1982) Liver regeneration studies with rat hepatocytes in primary culture. Cancer Res 42: 4673-4682. 
• Müller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188: 2033-2045. 
• Murata M, Kawanishi S (2000) Oxidative DNA damage by vitamin A and its derivative via superoxide generation. J Biol Chem 275: 2003-2008. 
• Musallam L, Ethier C, Haddad PS, Bilodeau M (2001) Role of EGF receptor tyrosine kinase activity in antiapoptotic effect of EGF on mouse hepatocytes. Am J Physiol Gastrointest Liver Physiol 280: G1360-G1369.  
• Oberhammer FA, Pavelka M, Sharma S, Tiefenbacher R, Purchio AF, Bursch W, Schulte-Hermann R (1992) Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci 89: 5408-5412. 
• Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL Jr., Valanis B, Williams JH Jr., Barnhart S, Cherniack MG, Brodkin CA, Hammar S (1996) Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial. J Natl Cancer Inst 88: 1550-1559.  
• Olson JA, Krinsky NI (1995) Introduction: The colourful, fascinating world of the carotenoids: important physiologic modulators. FASEB J 9: 1547-1550. 
• Rauscher R, Edenharder R, Platt KL (1998) In vitro antimutagenic and in vivo anticlastogenic effects of carotenoids and solvent extracts from fruits and vegetables rich in carotenoids. Mutat Res 413: 129-142.  
• Salgo MG, Pryor WA (1996) Trolox inhibits peroxinitrite-mediated oxidative stress and apoptosis in rat thymocytes. Arch Biochem Biophys 333: 482-488. 
• Sandoval M, Zhang X-J, Liu X, Mannick EE, Clark DA, Miller MJS (1997) Peroxynitrite-induced apoptosis in T84 and RAW 264.7 cells: attenuation by L-ascorbic acid. Free Radic Biol Med 22: 489-495. 
• Sharma R, Sharma A, Dwivedi S, Zimniak P, Awasthi S, Awasthi YC (2008) 4-Hydroxynonenal self-limits Fas-mediated DISC-independent apoptosis by promoting export of Daxx from the nucleus to the cytosol and its binding to Fas. Biochemistry 47: 143-156. 
• Siems WG, Sommerburg O, Hurst JS, van Kuijk FJ (2000) Carotenoid oxidative degradation products inhibit Na+-K+-ATPase. Free Radic Res 33: 427-435. 
• Siems W, Sommerburg O, Schild L, Augustin W, Langhans CD, Wiswedel I (2002) Beta-carotene cleavage products induce oxidative stress in vitro by impairing mitochondrial respiration. FASEB J 16: 1289-1291. 
• Sies H, Stahl W, Sundquist AR (1992) Antioxidant functions of vitamins. Vitamins E and C, beta- and other carotenoids. Ann N Y Acad Sci 669: 7-20. 
• Sommerburg O, Langhans C-D, Arnhold J, Leichsenring M, Salerno C, Crifo C, Hoffmann GF, Debatin K-M, Siems WG (2003) β-Carotene cleavage products after oxidation mediated via hypochlorous acid - a model for neutrophil-derived degradation. Free Radic Biol Med 35: 1480-1490. 
• Sprince H, Parker CM, Smith GG, Gonzales LJ (1975) Protective action of ascorbic acid and sulphur compounds against acetaldehyde toxicity: implication in alcoholism and smoking. Inflamm Res 5: 164-173.
• Traber MG (2004) Vitamin E, nuclear receptors and xenobiotic metabolism. Arch Biochem Biophys 423: 6-11. 
• Vakkila J, Lotze MT (2004) Inflammation and necrosis promote tumour growth. Nat Rev Immunol 4: 641-648. 
• Wang XD, Russell RM (1999) Procarcinogenic and anticarcinogenic effects of b-carotene. Nutr Rev 57: 263-272.  
• Watanabe M, Sugimoto M, Ito K (1992) The acrolein cytotoxicity and cytoprotective action of α-tocopherol. Gastroenterol Jpn 27: 199-205. 
• Wu TW, Hashimoto N, Wu J, Carey D, Li RK, Mickle DA, Weisel RD (1990) The cytoprotective effect of Trolox demonstrated with three types of human cells. Biochem Cell Biol 68: 1189-1194. 
• Zafarullah M, Li WQ, Sylvester J, Ahmad M (2003) Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 60: 6-20. 
• Zong W-X, Ditsworth D, Bauer DE, Wang Z-Q, Thompson CB (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 18: 1272-1282.