Valproinsäure pp 225-236 | Cite as

Einfluß von Valproinsäure auf Fettstoffwechsel und Carnitin

  • M. C. Laub
Conference paper

Zusammenfassung

1.Unter Valproinsäureeinfluß lassen sich im Tierversuch charakteristische Veränderungen im Zytosol (mikrovesikuläre Steatosis, vorwiegend periportal), an den Mitochondrien (numerische Zunahme, Größenzunahme, erhöhter Proteingehalt, Myeloideinlagerungen) und an den Peroxysomen (Größenzunahme, numerische Zunahme) darstellen, vorwiegend in Leber und Niere. Humanpathologische Befunde sind spärlich und betreffen fast ausschließlich Patienten mit fataler hepatotoxischer Reaktion. Gefunden wurden mikro vesikuläre Fetteinlagerungen, Nekrosen und Zirrhosen. Die humanpathologischen Befunde sind nicht einheitlich.

2.Wichtige VPA-induzierte Veränderungen im Intermediärstoffwechsel sind Verminderung der Fettsäureoxydation, Fettsäuresynthese, Ketogenese und Glukoneogenese. Freies CoA ist vermindert verfügbar. Die Bedeutung solcher Veränderungen, die zum Teil auch beim Menschen nachgewiesen wurden, ist unklar.

3.VPA führt im Tiermodell und bei Menschen zu erniedrigten Spiegeln von Gesamt-CA, freiem CA und kurzkettigem Acyl-CA. Beim Menschen ist die Hypocarnitinämie während VPA-Therapie zwar signifikant, jedoch milde ausgeprägt. Es gibt Hinweise darauf, daß es sich um ein transitorisches Phänomen handelt. Klinische Erscheinungen eines Carnitinmangels treten nicht auf.

4.Eine generelle Carnitinsubstitution während VPA-Therapie ist nach den gegenwärtig vorliegenden Befunden nicht indiziert.

5.Die Bedeutung der biochemisch faßbaren Veränderungen im Intermediärstoffwechsel für die Ätiologie einer VPA-bedingten hepatotoxischen Reaktion ist noch unklar. Es ist unwahrscheinlich, daß ein VPA-bedingter Carnitinmangel alleine für die Entwicklung einer hepatotoxischen Reaktion verantwortlich sein kann. Möglicherweise spielen die hier beschriebenen Stoffwechselveränderungen jedoch eine gewisse pathogenetische Rolle in einem multifaktorierten Zusammenspiel, welches zu einer hepatotoxischen Reaktion führen könnte.

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Literatur

  1. Alonso E, Girbés J, García-Espano A, Rubio V (1989) Changes in urea cycle-related metabolites in the mouse after combined administration of valproic acid and an amino acid load. Arch Biochem Biophys 272:267–273PubMedCrossRefGoogle Scholar
  2. Becker C-M, Harris RA (1983) Influence of valproid acid on hepatic carbohydrate and lipid metabolism. Arch Biochem Biophys 223:381–392PubMedCrossRefGoogle Scholar
  3. Bolanos JP, Medina JM, Williamson DH (1990) Inhibition of sterol but not fatty acid synthesis by valproate in developing rat brain in vivo. Biochem J 272:251–253PubMedGoogle Scholar
  4. Beghi E, Bizzi A, Codegoni AM, Trevisan D, Torri W (1990) Valproate, carnitine metabolism and biochemical indicators of liver function. Epilepsia 31:346–352PubMedCrossRefGoogle Scholar
  5. Böhles, H, Richter K, Wagner-Thiessen E, Schäfer H (1982) Decreased serum carnitine in valproate induced Reye syndrome. Eur J Pediatr 139:185–186PubMedCrossRefGoogle Scholar
  6. Bjorge SM, Baillie TA (1985) Inhibition of medium L chain fatty acid ß-oxidation in vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid. Biochem Biophys Res Commun 132:245–252PubMedCrossRefGoogle Scholar
  7. Camina MF, Rozas J, Castro-Gago M, Paz JM, Alonso C, Rodriguez-Segade S (1991) Alteration of renal carnitine metabolism by anticonvulsant treatment. Neurology 41:1444–1448PubMedCrossRefGoogle Scholar
  8. Camina MF, Rozas J, Gómez M, Paz JM, Alonso C, Rodriguez-Segade S (1991) Shortterm effects of administration of anticonvulsant drugs on free carnitine and acylcarnitine in mouse serum and tissues. Br J Pharmacol 103:1179–1183PubMedCrossRefGoogle Scholar
  9. Costell M, O’Connor J-E, Niguez M-P, Grisolía S (1984) Effects of L-carnitine on urea synthesis following acute ammonia intoxication in mice. Biochem Biophys Res Commun 120:726–733PubMedCrossRefGoogle Scholar
  10. Coudé FX, Grimber F, Pelet A, Benoit Y (1983) Action of the antiepileptic drug, valproic acid, on fatty acid oxidation in isolated rat hepatocytes. Biochem Biophys Res Commun 115:730–736PubMedCrossRefGoogle Scholar
  11. Coulter DL (1984) Carnitine deficiency: A possible mechanism for valproate hepatotoxicity (letter). Lancet 1:689PubMedCrossRefGoogle Scholar
  12. Dickinson RG, Hooper WD, Dunstan PR, Eadie MJ (1989) Urinary excretion of valproate and some metabolites in chronically treated patients. Therap Drug Monit 11:127–133CrossRefGoogle Scholar
  13. Di Donato S, Rimoldi M, Garavaglia B, Uziel G (1984) Propionylcarnitine excretion in propionic and methylmalonic acidurias: A cause of carnitine deficiency. Clin Chim Acta 139:13–21PubMedCrossRefGoogle Scholar
  14. Draye J-P, Vamecq J (1987) The inhibition by valproic acid of the mitchondrial oxidation of monocarboxylic and ω-hydroxylmonocarboxylic acids: Possible implications for the metabolism of γ-aminobutyric acid. J Biochem 102:235–242PubMedGoogle Scholar
  15. Dreifuss F, Langer DH (1987) Hepatic considerations in the use of antiepileptic drugs. Epilepsia 28 (Suppl):S23-S29PubMedCrossRefGoogle Scholar
  16. Grannemann GR, Wang S-J, Kesterson JW, Machinist JM (1984) The hepatotoxicity of valproic acid and its metabolites in rats. II. Intermediary and valproic acid metabolism. Hepatology 4:1153–1156CrossRefGoogle Scholar
  17. Hayasaka K, Takahashi J, Kobayashi Y, Junuma K, Narisawa K, Tada K (1986) Effects of valproate on biogenesis and function of liver mitochondria. Neurology 36:351–356PubMedCrossRefGoogle Scholar
  18. Horie S, Suga T (1985) Enhancement of peroxisomal ß-oxidation in the liver of rats and mice treated with valproic acid. Biochem Pharmacol 34:1357–1362PubMedCrossRefGoogle Scholar
  19. Kesterson JW, Grannemann GR, Machinist JM (1984) The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies. Hepatology 4:1143–1152PubMedCrossRefGoogle Scholar
  20. Kingsley E, Gray P, Tolman KG, Tweedale R (1983) The toxicity of metabolites of sodium valproate in cultured hepatocytes. J Clin Pharmacol 23:178–185PubMedCrossRefGoogle Scholar
  21. König S, Scheffner D, Rauterberg-Ruland J, Kochen W, Hofmann WJ, Wokittel E, Schick U (1983) Tödliches Leberversagen bei einem altersgemäß entwickelten fünf Jahre alten Jungen unter VPA-Monotherapie. Monatsschr Kinderheilk 135:310–313Google Scholar
  22. Laub MC, Paetzke-Brunner J, Jäger G (1986) Serum carnitine during valproic acid therapy. Epilepsia 27:559–562PubMedCrossRefGoogle Scholar
  23. Laub MC (1988) Ist eine Carnitinsubstitution bei Valproattherapie sinnvoll? EpilepsieBlätter 1:31–35Google Scholar
  24. Lin MH, Acheampong AA, Russell RG, Levy RH (1990) Effect of L-carnitine on hepatotoxicity and inhibition of fatty acid metabolism with valproate and ∆4-valproate (abstract). Epilepsia 31:600Google Scholar
  25. Matsuda J, Ohtani Y, Ninomiya N (1986) Renal handling of carnitine in children with carnitine deficiency and hyperammonemia associated with valproate therapy. J Pediatr 109:131–134PubMedCrossRefGoogle Scholar
  26. Melegh B, Kerner J, Kispál G, Acsádi G, Dani M (1987) Effect of chronic valproic acid treatment on plasma and urine carnitine levels in children: Decreased urinary excretion. Acta Paediatrica Hungarica 28:137–142PubMedGoogle Scholar
  27. Melegh B, Kerner J, Jaszar V, Bieber LL (1990a) Differential excretion of xenobiotic acyl-esters of carnitine due to administration of pivampicillin and valproate. Biochem Med Metab Biol 43:30–38PubMedCrossRefGoogle Scholar
  28. Melegh B, Kerner J, Ascádi G, Lakatos J, Sándor A (1990b) L-carnitine replacement therapy in chronic valproate treatment. Neuropediatrics 21:40–43PubMedCrossRefGoogle Scholar
  29. Moore KH, Decker BP, Schreefel FP (1988) Hepatic hydrolysis of octanoyl-CoA and valproyl-CoA in control and valproate-fed animals. Int J Biochem 20:175–178PubMedCrossRefGoogle Scholar
  30. Morita J, Yuge K, Yoshino M (1986) Hypocarnitinemia in the handicapped individuals who receive a polypharmacy of antiepileptic drugs. Neuropediatrics 17:203–205PubMedCrossRefGoogle Scholar
  31. Mortensen PB, Gregersen N, Kolvraa S, Christensen E (1980) The occurrence of C6-C10-dicarboxylic acids in urine from patients and rats treated with dipropylacetate. Biochem Med 24:153–161PubMedCrossRefGoogle Scholar
  32. Murakami K, Sugimoto T, Nishida N, Woo M, Araki A, Kobayashi Y, Sakane Y (1990) Carnitine metabolism and morphometric change of liver mitochondria in valproate-treated rats. Neuropediatrics 21:187–190PubMedCrossRefGoogle Scholar
  33. Murphy JV, Marquardt KM, Shug AL (1985) Valproic acid associated with abnormalities of carnitine metabolism (letter). Lancet 1:820–821PubMedCrossRefGoogle Scholar
  34. Nishida N, Sugimoto T, Araki A, Woo M, Sakane Y, Kobayashi Y (1987) Carnitine metabolism in valproate-treated rats: The effect of L-carnitine supplementation. Pediatr Res 22:500–503PubMedCrossRefGoogle Scholar
  35. Ohtani YF, Endo I, Matsuda I (1982) Carnitine deficiency and hyperammonemia associated with valproic acid therapy. J Pediatr 101:782–785PubMedCrossRefGoogle Scholar
  36. Olson MJ, Handler JA, Thurman RG (1986) Mechanism of zone-specific hepatic steatosis caused by valproate: Inhibition of ketogenesis in periportal regions of the liver lobule. Molec Pharmacol 30:520–525Google Scholar
  37. Opala G, Winter S, Vance C, Vance H, Hutchinson HT, Linn LS (1991) The effect of valproic acid on plasma carnitine levels. Amer J Dis Childh 145:999–1001Google Scholar
  38. Ponchaut S, Draye JP, Veitch K, Van Hoof F (1991) Influence of chronic administration of valproate on ultrastructure and enzyme content of peroxisomes in rat liver and kidney. Biochem Pharmacol 41:1419–1428PubMedCrossRefGoogle Scholar
  39. Powell-Jackson PR, Tredger JM, Williams R (1984) Hepatotoxicity to sodium valproate: A review. Gut 25:673–681Google Scholar
  40. Quistad GB, Staiger LE, Schooley DA (1986) The role of carnitine in the conjugation of acidic xenobiotics. Drug Metab Disposition 14:521–525Google Scholar
  41. Rebouche CJ, Engel AG (1983) Carnitine metabolism and deficiency syndromes. Mayo Clin Proc 58:533–540PubMedGoogle Scholar
  42. Rebouche CJ, Poulson DJ (1986) Carnitine metabolism and functions in humans. Ann Rev Nutr 6:41–66CrossRefGoogle Scholar
  43. Rodriguez-Segade S, de la Pena A, Tutor JC, Paz JM, Fernandez MP, Rozas J, Del Rio R (1989) Carnitine deficiency associated with anticonvulsant therapy. Clin Chim Acta 1981:175–182CrossRefGoogle Scholar
  44. Rozas J, Camina MF, Paz JM, Alonso C, Castro-Gago M, Rodriguez-Segade S (1989) Effects of acute valproate administration on carnitine metabolism in mouse serum and tissues. Biochem Pharmacol 39:181–185CrossRefGoogle Scholar
  45. Schmidt-Sommerfeld E, Penn D (1986) Carnitinmangel. Monatschr Kinderheilk 134: 224–231Google Scholar
  46. Shumate JB, Dodson WE, Brooke MH, Santiago J (1981) Suppression of fatty acid oxidation by valproic acid (abstract). Ann Neurol 10:88Google Scholar
  47. Singh Y, Lin GA, Krishna G (1987) Valproic acid-induced increase in acetyltransferase in rat hepatocytes is not due to an induction of peroxisomes. J Toxicol Environ Health 22:459–469PubMedCrossRefGoogle Scholar
  48. Suchy FJ, Ballistreri WF, Buchino JJ, Sondheimer JM, Bates SR, Kearns GL, Stull JD, Bove KE (1979) Acute hepatic failure associated with the use of sodium valproate. Report of two fatal cases. New Engl J Med 300:962–966PubMedCrossRefGoogle Scholar
  49. Stiemer B (1989) Morphological evaluation of steatosis in monolayer cultures (MDCK cells) after treatment with gentamicin and valproic acid. Histol Histopath 4:421–428Google Scholar
  50. Sugimoto T, Woo M, Nishida N, Takeuchi T, Sakane Y, Kobayashi Y (1987a) Hepatotoxicity in rat following administration of valproic acid. Epilepsia 28:142–146PubMedCrossRefGoogle Scholar
  51. Sugimoto T, Araki A, Nishida N, Sakane Y, Woo M, Takeuchi T, Kobayashi Y (1987b) Hepatotoxicity in rat following administration of valproic acid: Effect of L-carnitine supplementation. Epilepsia 28:373–377PubMedCrossRefGoogle Scholar
  52. Takeuchi T, Sugimoto T, Nishida N, Kobayashi Y (1988a) Evaluation of the cytotoxicity of sodium valproate on primary cultured rat hepatocytes. Neuropediatrics 19:158–161PubMedCrossRefGoogle Scholar
  53. Takeuchi T, Sugimoto T, Nishida N, Kobayashi Y (1988b) Protective effect of D, L-carnitine on valproate-induced hyperammonemia and hypoketonemia in primary cultured rat hepatocytes. Biochem Pharmacol 37:2255–2258PubMedCrossRefGoogle Scholar
  54. Thom H, Carter PE, Cole GF, Stevenson KL (1991) Ammonia and carnitine concentrations in children treated with sodium valproate compared with other anticonvulsant drugs. Developm Med Child Neurol 33:795–802CrossRefGoogle Scholar
  55. Thurston JH, Carroll JE, Dodson WE, Hauhart RE, Tasch V (1983) Chronic valproate administration reduces fasting ketonemia in children. Neurology 33:1348–1350PubMedCrossRefGoogle Scholar
  56. Thurston JH, Carroll JE, Hauhart RE, Schiro JA (1985) A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance. Life Sci 36:1643–1651PubMedCrossRefGoogle Scholar
  57. Thygesen J, Boesen F (1982) 2 cases of reversible liver lesion induced by valproate. Acta Neurol Scand 60:396–399Google Scholar
  58. Turnbull DM, Bone AJ, Bartlett K, Koundakjian PP, Sherratt HSA (1983) The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochem Pharmacol 32:1887–1892PubMedCrossRefGoogle Scholar
  59. Van den Branden C, Roels F (1985) Peroxisomal ß-oxidation and sodium valproate. Biochem Pharmacol 34:2147–2149CrossRefGoogle Scholar
  60. Ware S, Millward-Sadler GH (1989) Acute liver disease associated with sodium valproate. Lancet II:1110–1113Google Scholar
  61. Winter SC, Szabo-Aczel S, Curry CJR, Hutchinson HT, Hogne R, Shug A (1987) Plasma carnitine deficiency. Clinical observations in 51 pediatric patients. Amer J Dis Childh 41:660–665Google Scholar
  62. Young RSK, Bergman I, Gang DL, Richardson EP (1980) Fatal Reye-like syndrome associated with valproic acid. Ann Neurol 7:389PubMedCrossRefGoogle Scholar
  63. Zimmermann HJ, Ishak KG (1982) Valproate-induced hepatic injury: Analysis of 23 fatal cases. Hepatology 2:591–597CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

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  • M. C. Laub

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