Advertisement

European Journal of Clinical Pharmacology

, Volume 43, Issue 6, pp 639–642 | Cite as

Failure of N-acetylcysteine to reduce low-density lipoprotein oxidizability in healthy subjects

  • H. A. Kleinveld
  • P. N. M. Demacker
  • A. F. H. Stalenhoef
Originals

Summary

We have studied the effects of N-acetylcysteine which is thought to have antioxidant properties, on the susceptibility of low-density lipoprotein to oxidation and on whole-blood glutathione concentrations in six healthy volunteers.

N-acetylcysteine was given orally in a dosage of at 1.2 g per day for 4 weeks, followed by 2.4 g per day for a further two weeks. The susceptibility of low-density lipoprotein toin vitro Cu2+-oxidation was determined by continuously measuring the formation of conjugated dienes. Whole-blood concentrations of reduced and oxidized glutathione were also determined.

N-acetylcysteine had no effect on the susceptibility of LDL to oxidation. Concentrations of vitamin E in the serum and in low-density lipoprotein were not changed. Compared with controls the concentration of glutathione in N-acetylcysteine treated subjects was reduced (−48 %) and the concentration of oxidized glutathione was higher (+80%). The GSH/GSSG-ratio, a marker of oxidative stress was 83 % lower.

The results do not support the supposed antioxidative action of N-acetylcysteine. It seems more likely that N-acetylcysteine acts as a pro-oxidant in the dosage used.

Key words

N-acetylcysteine, Glutathione, Low-density lipoprotein atherosclerosis, anti-oxidant, healthy volunteers 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Boman R, Backer U, Larsson S, Melander B and Wahlander L (1983) Oral acetylcysteine reduces exacerbation rate in chronic bronchitis. Eur J Resp Dis 64:405–415Google Scholar
  2. Bridgeman MME, Marsden M, MacNee W, Flenley DC, Ryle AP (1991) Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax 46:39–112Google Scholar
  3. Carew TE, Schwenke DC, Steinberg D (1987) Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidantsin vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemie rabbit. Proc Natl Acad Sci USA 84:7725–7729Google Scholar
  4. Ceconi C, Curello S, Cargoni A, Ferrari R, Albertini A, Visioli O (1988) The role of glutathione status in the protection against ischaemic and reperfusion damage: effects of n-acetylcysteine. J Mol Cell Cardiol 20:5–13Google Scholar
  5. Corcoran GB, Wong BK (1986) Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteinein vivo: studied with N-acetyl-D-cysteine. J Pharmacol Exp Ther 238:54–61Google Scholar
  6. Curello S, Ceconi C, Cargnoni A, Cornacchiari A, Ferrari R. Albertini A (1987) Improved procedure for determining glutathione in plasma as an index of myocardial oxidative stress. Clin Chem 33:1448–1449Google Scholar
  7. De Graaf J, Hak-Lemmers HLM, Hectors MPC, Demacker PNM, Hendriks JCM, Stalenhoef AFH (1991) Enhanced susceptibility toin vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arteriosclerosis and Thrombosis 11:298–306Google Scholar
  8. Esterbauer H, Dieber-Rotheneder M, Waeg G, Striegl G, Eirgens G (1990) Biochemical, structural and functional properties of oxidized low-density lipoprotein. Chem Res Toxicol 3:77–92Google Scholar
  9. Esterbauer H, Striegl G, Puhl H, Rotheneder M (1989) Continuous monitoring ofin vitro oxidation of human low density lipoprotein. Free Radical Res Commun 6:67–75Google Scholar
  10. Gavish D, Breslow J (1991) Lipoprotein(a) reduction by N-acetylcysteine. Lancet 337: 203–204Google Scholar
  11. Griffith OW (1985) Glutathione and glutathione disulfide. In: Bergmeyer HU (ed) Methods of enzymatic analysis. VCH, WeinheimGoogle Scholar
  12. Henriksen T, Mahoney EM, Steinberg D (1981) Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci USA 78:6499–6503Google Scholar
  13. Lauterburg BH, Corcoran GB, Mitchell JR (1983) Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in ratsin vivo. J Clin Invest 71:980–991Google Scholar
  14. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  15. MÅrtensson J, Gustafsson J, Larsson A (1989) A therapeutic trial with N-acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5-oxoprolinuria). J Inher Metab Dis 12:120–130Google Scholar
  16. Multicenter Study Group (1980) Long-term acetylcysteine in chronic bronchitis. Eur J Resp Dis 61 [Suppl.]:93–108Google Scholar
  17. Parthasarathy S (1987) Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL-receptor. Biochim Biophys Acta 917:337–340Google Scholar
  18. Parthasarathy S, Printz DJ, Boyd D, Joy L, Steinberg D (1986) Macrophage oxidation of low density lipoprotein generates a modified form recognized by the scavenger receptor. Arteriosclerosis 6:505–510Google Scholar
  19. Parthasarathy S, Young S, Witztum JL, Pittman RC, Steinberg D (1986) Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest 77:641–644Google Scholar
  20. Perchellet EM, Maatta EA, Abney NL, Perchellet JP (1987) Effects of diverse intracellular thiol delivery agents on glutathione peroxidase activity, the ratio to reduced/oxidized glutathione, and ornithine decarboxylase induction in isolated mouse epidermal cells treated with 12-O-tetradecanoylphorbol-13-acetate. J Cell Physiol 131:64–73Google Scholar
  21. Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, Proudfoot AT (1979) Intravenous N-acetylcysteine: the treatment of coite for paracetamol poisoning. Br Med J 2:1097–1100Google Scholar
  22. Saez G, Thornalley PJ, Hill HAO, Hems R, Bannister JV (1982) The production of free radicals during the auto-oxidation of cysteine and their effect on isolated rat hepatocytes. Biochim Biophys Acta 719:24–31Google Scholar
  23. Sheffner AL (1963) The reductionin vitro in viscosity of mucoprotein solutions by a new mucolytic agent, N-acetyl-L-cysteine. Ann NY Acad Sci 106:298–310Google Scholar
  24. Stalenhoef AFH, Kroon AA, Demacker PNM (1991) N-acetylcysteine and lipoprotein. Lancet 337:491Google Scholar
  25. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL (1989) Beyond cholesterol. Modification of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915–924Google Scholar
  26. Steinbrecher U, Partahasarathy S, Leake DS, Witztum JL, Steinberg D (1984) Modification of low density lipoprotein by endothelial cells involves lipidperoxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 81:3883–3887Google Scholar
  27. Sunde RA, Hoekstra WG (1980) Structure, synthesis and function of glutathione peroxidase. Nutrition Reviews 38:265–273Google Scholar
  28. Tietze F (1969) Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione. Anal Biochem 27:502–522Google Scholar
  29. Viña J, Saez GT, Wiggins D, Roberts AFC, Hems R, Krebs HA (1983) The effect of cysteine oxidation on isolated hepatocytes. Biochem J 212:39–44Google Scholar
  30. Ylä-Herttuala S, Palinsky W Rosenfeld, Parthasarathy S, Carew TE, Butler S, Steinberg D (1989) Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 84:1086–1095Google Scholar

Copyright information

© Springer-Veriag 1992

Authors and Affiliations

  • H. A. Kleinveld
    • 1
  • P. N. M. Demacker
    • 1
  • A. F. H. Stalenhoef
    • 1
  1. 1.Department of General Internal MedicineUniversity Hospital, NijmegenNijmegenThe Netherlands

Personalised recommendations