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AGE

, Volume 34, Issue 1, pp 181–193 | Cite as

Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids

  • Estelle Pujos-Guillot
  • Gisèle Pickering
  • Bernard Lyan
  • Gilles Ducheix
  • Marion Brandolini-Bunlon
  • Françoise Glomot
  • Dominique Dardevet
  • Claude Dubray
  • Isabelle Papet
Article

Abstract

Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on metabolic and nutritional aspects. Effects of 3 g/day paracetamol for 14 days on fasting blood glutathione, plasma amino acids and sulfate, urinary paracetamol metabolites, and urinary metabolomic were studied in independently living older persons (five women, five men, mean (±SEM) age 74 ± 1 years). Dietary intakes were recorded before and at the end of the treatment and ingested sulfur amino acids were evaluated. Fasting blood glutathione, plasma amino acids, and sulfate were unchanged. Urinary nitrogen excretion supported a preservation of whole body proteins, but large-scale urinary metabolomic analysis revealed an oxidation of some sulfur-containing compounds. Dietary protein intake was 13% higher at the end than before paracetamol treatment. Final sulfur amino acid intake reached 37 mg/kg/day. The increase in sulfur amino acid intake corresponded to half of the sulfur excreted in urinary paracetamol conjugates. In conclusion, older persons accommodated to long-term paracetamol treatment by increasing dietary protein intake without any mobilization of body proteins, but with decreased anti-oxidative defenses. The extra demand in sulfur amino acids led to a consumption far above the corresponding population-safe recommendation.

Keywords

Detoxification Glutathione Metabolomic Older persons Paracetamol Sulfur amino acids requirement 

Notes

Acknowledgments

We thank all persons who collaborated in the study, especially Bertille Lamandé for clinical study setting-up, Nordine Hafnaoui for amino acid analysis, Jean-François Martin for statistical analysis of metabolomic raw data, Charlotte Joly for large-scale metabolomic analysis, Hélène Lafarge for literature acquisition and the volunteers who participated in the study. The research was supported by the Institut National de la Recherche Agronomique (INRA), France.

References

  1. Bannwarth B, Pehourcq F, Lagrange F, Matoga M, Maury S, Palisson M, Le Bars M (2001) Single and multiple dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain. J Rheumatol 28:182–184PubMedGoogle Scholar
  2. Benedetti MS, Whomsley R, Canning M (2007) Drug metabolism in the paediatric population and in the elderly. Drug Discov Today 12:599–610PubMedCrossRefGoogle Scholar
  3. Block RJ, Weiss KW (1956) Amino Acid Handbook. Thomas CC, Springfield, Illinois, USAGoogle Scholar
  4. Burgunder JM, Varriale A, Lauterburg BH (1989) Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol 36:127–131PubMedCrossRefGoogle Scholar
  5. Buttar HS, Chow AY, Downie RH (1977) Glutathione alterations in rat liver after acute and subacute oral administration of paracetamol. Clin Exp Pharmacol Physiol 4:1–6PubMedCrossRefGoogle Scholar
  6. Chen LH, Liu S, Newell ME, Barnes K (1985) Survey of drug use by the elderly and possible impact of drugs on nutritional status. Drug Nutr Interact 3:73–86PubMedGoogle Scholar
  7. Chen TS, Richie JPJ, Lang CA (1990) Life span profiles of glutathione and acetaminophen detoxification. Drug Metab Dispos 18:882–887PubMedGoogle Scholar
  8. Chen TS, Richie JP, Nagasawa HT, Lang CA (2000) Glutathione monoethyl ester protects against glutathione deficiencies due to aging and acetaminophen in mice. Mech Ageing Dev 120:127–139PubMedCrossRefGoogle Scholar
  9. Chen C, Krausz KW, Idle JR, Gonzalez FJ (2008) Identification of novel toxicity-associated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2e1-null mice. J Biol Chem 283:4543–4559PubMedCrossRefGoogle Scholar
  10. Critchley JA, Nimmo GR, Gregson CA, Woolhouse NM, Prescott LF (1986) Inter-subject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol 22:649–657PubMedGoogle Scholar
  11. Di Buono M, Wykes LJ, Ball RO, Pencharz PB (2001) Total sulfur amino acid requirement in young men as determined by indicator amino acid oxidation with L-[1-C-13] phenylalanine. Am J Clin Nutr 74:756–760PubMedGoogle Scholar
  12. Di Pietra AM, Gatti R, Andrisano V, Cavrini V (1996) Application of high-performance liquid chromatography with diode-array detection and on-line post-column photochemical derivatization to the determination of analgesics. J Chromatogr A 729:355–361PubMedCrossRefGoogle Scholar
  13. Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedGoogle Scholar
  14. Dröge W (2005) Oxidative stress and ageing: is ageing a cysteine deficiency syndrome? Philos Trans R Soc B Biol Sci 360:2355–2372CrossRefGoogle Scholar
  15. Favier JC, Ireland-Ripert J, Toque C, Feinberg M (1995) Répertoire général des aliments (REGAL): table de composition. INRA-AFSSA-CIQUAL-TEC & DOC, ParisGoogle Scholar
  16. Forrest JA, Clements JA, Prescott LF (1982) Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 7:93–107PubMedCrossRefGoogle Scholar
  17. Fulgoni VL3 (2008) Current protein intake in America: analysis of the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr 87:1554S–1557SPubMedGoogle Scholar
  18. Gaitonde MK (1967) A spectrometric method for the direct determination of cysteine in the presence of other naturally occurring amino acids. Biochem J 104:627–633PubMedGoogle Scholar
  19. Graham GG, Day RO, Graudins A, Mohamudally A (2010) FDA proposals to limit the hepatotoxicity of paracetamol (acetaminophen): are they reasonable? Inflammopharmacol 18:47–55CrossRefGoogle Scholar
  20. Hart SJ, Calder IC, Tange JD (1982) The metabolism and toxicity of paracetamol in Sprague–Dawley and Wistar rats. Eur J Drug Metab Pharmacokinet 7:203–222PubMedCrossRefGoogle Scholar
  21. Hazelton GA, Hjelle JJ, Klaassen CD (1986) Effects of cysteine pro-drugs on acetaminophen-induced hepatotoxicity. J Pharmacol Exp Ther 237:341–349PubMedGoogle Scholar
  22. Hercberg S, Deheeger M, Preziosi P (1994) SU.VI.MAX. Portions alimentaires. Manuel photos pour l'estimation des quantités. Poly Technica, ParisGoogle Scholar
  23. Johnson KA, Plumb R (2005) Investigating the human metabolism of acetaminophen using UPLC and exact mass oa-TOF MS. J Pharm Biomed Anal 39:805–810PubMedCrossRefGoogle Scholar
  24. Julius M, Lang CA, Gleiberman L, Harburg E, DiFranceisco W, Schork A (1994) Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol 47:1021–1026PubMedCrossRefGoogle Scholar
  25. Klotz U (2009) Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 41:67–76PubMedCrossRefGoogle Scholar
  26. Kurpad AV, Regan MM, Varalakshmi S, Vasudevan J, Gnanou J, Raj T, Young VR (2003) Daily methionine requirements of healthy Indian men, measured by a 24-h indicator amino acid oxidation and balance technique. Am J Clin Nutr 77:1198–1205PubMedGoogle Scholar
  27. Lauterburg BH, Mitchell JR (1987) Therapeutic doses of acetaminophen stimulate the turnover of cystin and glutathione in man. J Hepatol 4:206–211PubMedCrossRefGoogle Scholar
  28. Le Moullec N, Deheeger M, Preziosi P, Monteiro P, Valeix P, Rolland-Cachera MF, De Courcy GP, Christides JP, Cherouvrier F, Galan P, Hercberg S (1996) Validation du manuel-photos utilisé pour l'enquete alimentaire de l'etude SU.VI.MAX (Validation of photographic document used to estimate the amounts of foods eaten by subjects in the suvimax study.). Cah Nutr Diet 31:158–164Google Scholar
  29. Maher P (2005) The effects of stress and aging on glutathione metabolism. Ageing Res Rev 4:288–314PubMedCrossRefGoogle Scholar
  30. Malloy MH, Rassin DK, Gaull GE (1981) A method for measurement of free and bound plasma cyst(e)ine. Anal Biochem 113:407–415PubMedCrossRefGoogle Scholar
  31. Malmezat T, Breuillé D, Pouyet C, Patureau Mirand P, Obled C (1998) Metabolism of cysteine is modified during the acute phase of sepsis in rats. J Nutr 128:97–105PubMedGoogle Scholar
  32. Mannery YO, Ziegler TR, Park Y, Jones DP (2010) Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans. J Pharmacol Exp Ther 333:939–947PubMedCrossRefGoogle Scholar
  33. McLean AE, Armstrong GR, Beales D (1989) Effect of d- or l-methionine and cysteine on the growth inhibitory effects of feeding 1% paracetamol to rats. Biochem Pharmacol 38:347–352PubMedCrossRefGoogle Scholar
  34. Mercier S, Breuillé D, Buffiere C, Gimonet J, Papet I, Patureau Mirand P, Obled C (2006) Methionine kinetics are altered in the elderly both in the basal state and after vaccination. Am J Clin Nutr 83:291–298PubMedGoogle Scholar
  35. Miners JO, Penhall R, Robson RA, Birkett DJ (1988) Comparison of paracetamol metabolism in young adult and elderly males. Eur J Clin Pharmacol 35:157–160PubMedCrossRefGoogle Scholar
  36. Obled C, Papet I, Breuillé D (2004) Sulfur-containing amino acids and glutathione in diseases. In: Cynober, L. A. (ed) Metabolic and therapeutic aspects of amino acids in clinical nutrition. CRC, pp 667–687Google Scholar
  37. Patureau Mirand P (2003) Les apports nutritionnels conseillés (ANC) en protéines. OCL Oleagineux Corps gras Lipides 10:61–65Google Scholar
  38. Pickering G (2004) Frail elderly, nutritional status and drugs. Arch Gerontol Geriatr 38:174–180PubMedCrossRefGoogle Scholar
  39. Prescott LF (2000) Paracetamol, alcohol and the liver. Br J Clin Pharmacol 49:291–301PubMedCrossRefGoogle Scholar
  40. Prescott L (2005) Oral or intravenous N-acetylcysteine for acetaminophen poisoning? Ann Emerg Med 45:409–413PubMedCrossRefGoogle Scholar
  41. Raynaud A, Revel-Delhom C, Alexandre D, Alix E, Ancellin R, Bouteloup C, Brocker P, Chapiro S, Dumarcet N, Haslé A, Lecocq JM, Lefevre MP, l'Hermine A, Lurcel J, Ménivard N, Perette MA, Perrin AM, Hébuterne X (2007) Stratégies de prise en charge en cas de dénutrition protéino-énergetique de la personne âgée. Nutr Clin Metab 21:120–133Google Scholar
  42. Reicks M, Hathcock JN (1989) Prolonged acetaminophen ingestion in mice: effects on the availability of methionine for metabolic functions. J Nutr 119:1042–1049PubMedGoogle Scholar
  43. Richie JPJ, Lang CA, Chen TS (1992) Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Biochem Pharmacol 44:129–135PubMedCrossRefGoogle Scholar
  44. Rousset S, Patureau Mirand P, Brandolini M, Martin JF, Boirie Y (2003) Daily protein intakes and eating patterns in young and elderly french. Br J Nutr 90:1107–1115PubMedCrossRefGoogle Scholar
  45. Slattery JT, Wilson JM, Kalhorn TF, Nelson SD (1987) Dose-dependent pharmacokinetics of acetaminophen—evidence of glutathione depletion in humans. Clin Pharmacol Ther 41:413–418PubMedCrossRefGoogle Scholar
  46. Sun J, Schnackenberg LK, Holland RD, Schmitt TC, Cantor GH, Dragan YP, Beger RD (2008) Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. J Chromatogr B 871:328–340CrossRefGoogle Scholar
  47. Trenti T, Bertolotti M, Castellana CN, Ferrari A, Pini LA, Sternieri E (1992) Plasma glutathione level in paracetamol daily abuser patients. Changes in plasma cysteine and thiol groups after reduced glutathione administration. Toxicol Lett 64–65:757–761PubMedCrossRefGoogle Scholar
  48. Winnike JH, Busby MG, Watkins PB, O'Connell TM (2009) Effects of a prolonged standardized diet on normalizing the human metabolome. Am J Clin Nutr 90:1496–1501PubMedCrossRefGoogle Scholar
  49. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N, Cheng D, Jewell K, Arndt D, Sawhney S, Fung C, Nikolai L, Lewis M, Coutouly MA, Forsythe I, Tang P, Shrivastava S, Jeroncic K, Stothard P, Amegbey G, Block D, Hau DD, Wagner J, Miniaci J, Clements M, Gebremedhin M, Guo N, Zhang Y, Duggan GE, Macinnis GD, Weljie AM, Dowlatabadi R, Bamforth F, Clive D, Greiner R, Li L, Marrie T, Sykes BD, Vogel HJ, Querengesser L (2007) HMDB: the human metabolome database. Nucleic Acids Res 35:D521–D526PubMedCrossRefGoogle Scholar
  50. Wynne HA, Cope LH, Herd B, Rawlins MD, James OF, Woodhouse KW (1990) The association of age and frailty with paracetamol conjugation in man. Age Ageing 19:419–424PubMedCrossRefGoogle Scholar
  51. Zhao L, Pickering G (2011) Paracetamol metabolism and related genetic differences. Drug Metab Rev 43:41–52PubMedCrossRefGoogle Scholar
  52. Zhou XJ, Saxena R, Liu Z, Vaziri ND, Silva FG (2008) Renal senescence in 2008: progress and challenges. Int Urol Nephrol 40:823–839PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2011

Authors and Affiliations

  • Estelle Pujos-Guillot
    • 1
  • Gisèle Pickering
    • 2
  • Bernard Lyan
    • 1
  • Gilles Ducheix
    • 2
  • Marion Brandolini-Bunlon
    • 3
  • Françoise Glomot
    • 4
    • 5
  • Dominique Dardevet
    • 4
    • 5
  • Claude Dubray
    • 2
  • Isabelle Papet
    • 4
    • 5
  1. 1.Plateforme d’Exploration du Métabolisme, INRACentre Clermont-Ferrand—Theix, UMR 1019 Nutrition HumaineSaint-Genès-ChampanelleFrance
  2. 2.Centre de Pharmacologie Clinique, Inserm CIC 501, INSERM U766, Faculté de MédecineClermont-FerrandFrance
  3. 3.CRNH Auvergne, Unité d’Exploration en NutritionClermont-FerrandFrance
  4. 4.INRA, Centre Clermont-Ferrand—TheixUMR 1019 Unité de Nutrition HumaineSaint-Genès-ChampanelleFrance
  5. 5.Univ Clermont 1, UFR Médecine, UMR 1019, Unité Nutrition HumaineClermont-FerrandFrance

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