Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 375, Issue 6, pp 401–406 | Cite as

Unchanged serum levels of advanced glycation endproducts in patients with liver disease

  • Moritz Butscheid
  • Christian Schäfer
  • Stefanie Brenner
  • Dominik Alscher
  • Thomas Mürdter
  • Toshimitsu Niwa
  • Matthias Frischmann
  • Monika Pischetsrieder
  • Ulrich Klotz
Original Article

Abstract

Advanced glycation end products (AGEs), e.g., carboxymethyllysine (CML) or imidazolone are involved in several age-related disorders. Concerning their accumulation, the importance of hepatic and renal function is controversially discussed. To test whether impairment of hepatic or renal function will affect their accumulation, both AGEs have been measured in various populations, such as 52 patients with liver disease [viral hepatitis C without (n = 19) and with (n = 10) fatty liver; nonalcoholic fatty liver (n = 13), nonalcoholic steatohepatitis (n = 10)]. Serum concentrations of both AGEs have been compared to those in 20 healthy controls and 24 patients with moderate renal impairment (creatinine clearance 23–55 ml/min). Concerning CML (95% C.I. 803–1200 ng/ml), no differences between the various groups could be observed. Likewise, serum levels of imidazolone (95% C.I. 1.3–5.6 units) were similar in all populations. In conclusion, moderate impairment in hepatic or in renal function did not affect serum levels of CML and imidazolone. Apparently, any increase observed in severe cirrhosis or renal failure seems to be rather a consequence than a cause of both disorders.

Keywords

Carboxymethyllysine Imidazalone Accumulation Liver disease Renal impairment Elimination 

Notes

Acknowledgments

The secretarial help of Mrs. U. Hengemühle and the laboratory assistance of Mrs. S. Gutzeit and Mrs. M. Deckert are highly appreciated. We thank MicroCoat Biotechnologie GmbH for providing the imidazolone ELISA. The study was supported by the Doktor Robert Pfleger-Foundation Bamberg and the Robert Bosch Foundation, Germany.

Conflict of interest statement

All authors declare no conflict of interest.

References

  1. Ahmed MU, Brinkmann FE, Degenhardt TP, Thorpe SR, Baynes JW (1997) N-epsilon-(carboxymethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins. Biochem J 324:565–570PubMedGoogle Scholar
  2. Ahmed N, Thornalley PJ, Lüthen R, Häussinger D, Sebekova K, Schinzel R et al (2004) Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effects of cirrhosis. J Hepatol 41:913–919PubMedCrossRefGoogle Scholar
  3. Baynes JW (2001) The role of AGEs in aging: causation or correlation. Exp Gerontol 361:1527–1537CrossRefGoogle Scholar
  4. Dilger K, Metzler J, Bode JC, Klotz U (1997) CYP2C1 activity in patients with alcoholic liver disease. J Hepatol 27:1009–1014PubMedCrossRefGoogle Scholar
  5. Dukic-Stefanovic S, Schinzel R, Riederer P, Münch G (2001) AGEs in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology 2:19–34PubMedCrossRefGoogle Scholar
  6. Frye RF, Zgheib NK, Matzke GR, Chaves-Gnecco D, Rabinovitz M, Shaik OS et al (2006) Liver disease selectivity modulates cytochrome P450-mediated metabolism. Clin Pharmacol Ther 80:235–245PubMedCrossRefGoogle Scholar
  7. Gerdemann A, Wagner Z, Solf A, Bahner U, Heidland A, Vienken J et al (2002) Plasma levels of advanced glycation end products during haemodialysis, haemodiafiltration and haemofiltration: potential importance of dialysate quality. Nephrol Dial Transplant 17:1045–1049PubMedCrossRefGoogle Scholar
  8. Harrison SA, Di Bisceglie AD (2003) Advances in the understanding and treatment of nonalcoholic fatty liver disease. Drugs 63:2379–2394PubMedCrossRefGoogle Scholar
  9. Heidland A, Sebekova K, Frangiosa A, De Santos LS, Cirillo M, Rossi F et al (2004) Paradox of circulating advanced glycation end product concentrations in patients with congestive heart failure and after transplantation. Heart 90:1269–1274PubMedCrossRefGoogle Scholar
  10. Horiuchi S (2002) The liver is the main site for metabolism of circulating advanced glycation end products. J Hepatol 36:123–125PubMedCrossRefGoogle Scholar
  11. Kasper M, Funk RHW (2001) Age-related changes in cells and tissues due to advanced glycation end products (AGEs). Arch Gerontol Geriatr 320:233–243CrossRefGoogle Scholar
  12. Matsumoto K, Sano H, Nagai R, Suzuki H, Kodama T,Yoshida M et al (2000) Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor class A. Biochem J 352 (part 1):233–240PubMedCrossRefGoogle Scholar
  13. Nakajou K, Horiuchi S, Sakai M, Hirata K, Tanaka M, Takeya M et al (2005) CD36 is not involved in scavenger receptor-mediated endocytic uptake of glycolaldehyde- and methylglyoxal-modified proteins by liver endothelial cells. J Biochem (Tokyo) 137:607–616Google Scholar
  14. Niwa T (2006) Mass spectrometry for the study of protein glycation in disease. Mass Spectrom Rev 25:713–723PubMedCrossRefGoogle Scholar
  15. Niwa T, Katzuki T, Miyazaki S, Miyazaki T, Ishizaki Y, Hayase F et al (1997a) Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients. J Clin Invest 99:1272–1280PubMedCrossRefGoogle Scholar
  16. Niwa T, Katsuzaki T, Ishizaki Y, Hayase F, Miyazaki T, Uematsu T et al (1997b) Imidazalone, a novel advanced glycation end product, is present at high levels in kidneys of rats with streptozotocin-induced diabetes. FEBS Lett 407:297–302PubMedCrossRefGoogle Scholar
  17. Schwenger V, Zeier M, Henle T, Ritz E (2001) Advanced glycation end products (AGEs) as uremic toxins. Nahrung 45:172–176PubMedCrossRefGoogle Scholar
  18. Šebeková K, Kupčová V, Schinzel R, Heidland A (2002) Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis - amelioration by liver transplantation. J Hepatol 36:66–71PubMedCrossRefGoogle Scholar
  19. Sitt AW, Jenkino AJ, Cooper ME (2002) Advanced glycation end products and diabetic complications. Expert Opin Investig Drugs 11:1205–1223CrossRefGoogle Scholar
  20. Smedsrød B, Melkko J, Araki N, Sano H, Horiuchi S (1997) Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells. Biochem J 322:567–573PubMedGoogle Scholar
  21. Svistounov D, Smedsrød B (2004) Hepatic clearance of advanced glycation end products (AGEs)—myth or truth? J Hepatol 41:103–1040CrossRefGoogle Scholar
  22. Svistounov DN, Berg TJ, McCourt PAG, Zykova SN, Elvevold KH, Nagai R et al (2003) Lack of recognition of Nepsilon-(carboxymethyl)lysine by the mouse liver reticulo-endothelial system: implications for pathophysiology. Biochem Biophys Res Comm 309:786–791PubMedCrossRefGoogle Scholar
  23. Tauer A, Knerr T, Niwa T, Schaub TP, Lage C, Passlick-Deetjen J et al (2001) In vitro formation of Nɛ-(carboxymethyl)lysine and imidazolones under conditions similar to continuous ambulatory peritoneal dialysis. Biochem Biophys Res Comm 280:1408–1411PubMedCrossRefGoogle Scholar
  24. Thornalley PJ, Battah S, Ahmed N, Karachalis N, Agalou S, Babaei-Jadid R et al (2003) Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem J 375:581–592PubMedCrossRefGoogle Scholar
  25. Traynor J, Mactier R, Geddes CC, Fox JG (2006) How to measure renal function in clinical practice. Br Med J 333:733–737CrossRefGoogle Scholar
  26. Vas T, Wagner Z, Jenei V, Varga Z, Kovacs T, Wittmann I et al (2005) Oxidative stress and non-enzymatic glycation in IgA nephropathy. Clin Nephrol 64:343–351PubMedGoogle Scholar
  27. Wagner Z, Wittmann I, Mazak I, Schinzel R, Heidland A, Kientsch-Engel R et al (2001) N(epsilon)-(carboxymethyl)lysine levels in patients with type 2 diabetes: role of renal function. Am J Kidney Dis 38:785–791PubMedGoogle Scholar
  28. Williams J, Topley N, Craig K, Mackenzie RK, Pischetsrieder M, Lage C et al (2004). The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane. Kidney Int 66:408–418PubMedCrossRefGoogle Scholar
  29. Zhang X, Frischmann M, Kientsch-Engel R, Steinmann K, Stopper H, Niwa T et al (2005) Two immunmochemical assays to measure advanced glycation end-products in serum from dialysis patients. Clin Chem Lab Med 43:503–511PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Moritz Butscheid
    • 1
    • 2
  • Christian Schäfer
    • 3
  • Stefanie Brenner
    • 1
    • 2
  • Dominik Alscher
    • 3
  • Thomas Mürdter
    • 1
    • 2
  • Toshimitsu Niwa
    • 4
  • Matthias Frischmann
    • 5
  • Monika Pischetsrieder
    • 5
  • Ulrich Klotz
    • 1
    • 2
  1. 1.Dr. Margarete Fischer-Bosch Institute of Clinical PharmacologyStuttgartGermany
  2. 2.University of TübingenTübingenGermany
  3. 3.Robert Bosch HospitalStuttgartGermany
  4. 4.Department of Clinical Preventive MedicineNagoya University HospitalNagoyaJapan
  5. 5.Institute of Pharmacy and Food ChemistryUniversity of Erlangen-NürnbergErlangenGermany

Personalised recommendations