Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1987 Feb 1;241(3):783–791. doi: 10.1042/bj2410783

Chlorpromazine and carnitine-dependency of rat liver peroxisomal beta-oxidation of long-chain fatty acids.

J Vamecq
PMCID: PMC1147631  PMID: 3593222

Abstract

The enzyme targets for chlorpromazine inhibition of rat liver peroxisomal and mitochondrial oxidations of fatty acids were studied. Effects of chlorpromazine on total fatty acyl-CoA synthetase activity, on both the first and the third steps of peroxisomal beta-oxidation, on the entry of fatty acyl-CoA esters into the peroxisome and on catalase activity, which allows breakdown of the H2O2 generated during the acyl-CoA oxidase step, were analysed. On all these metabolic processes, chlorpromazine was found to have no inhibitory action. Conversely, peroxisomal carnitine octanoyltransferase activity was depressed by 0.2-1 mM-chlorpromazine, which also inhibits mitochondrial carnitine palmitoyltransferase activity in all conditions in which these enzyme reactions are assayed. Different patterns of inhibition by the drug were, however, demonstrated for both these enzyme activities. Inhibitory effects of chlorpromazine on mitochondrial cytochrome c oxidase activity were also described. Inhibitions of both cytochrome c oxidase and carnitine palmitoyltransferase are proposed to explain the decreased mitochondrial fatty acid oxidation with 0.4-1.0 mM-chlorpromazine reported by Leighton, Persico & Necochea [(1984) Biochem. Biophys. Res. Commun. 120, 505-511], whereas depression by the drug of carnitine octanoyltransferase activity is presented as the factor responsible for the decreased peroxisomal beta-oxidizing activity described by the above workers.

Full text

PDF
787

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. DE DUVE C., PRESSMAN B. C., GIANETTO R., WATTIAUX R., APPELMANS F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955 Aug;60(4):604–617. doi: 10.1042/bj0600604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Debeer L. J., Thomas J., De Schepper P. J., Mannaerts G. P. Lysosomal triacylglycerol lipase and lipolysis in isolated rat hepatocytes. J Biol Chem. 1979 Sep 25;254(18):8841–8846. [PubMed] [Google Scholar]
  3. Duve C. Exploring cells with a centrifuge. Science. 1975 Jul 18;189(4198):186–194. doi: 10.1126/science.1138375. [DOI] [PubMed] [Google Scholar]
  4. Fahimi H. D., Reinicke A., Sujatta M., Yokota S., Ozel M., Hartig F., Stegmeier K. The short- and long-term effects of bezafibrate in the rat. Ann N Y Acad Sci. 1982;386:111–135. doi: 10.1111/j.1749-6632.1982.tb21410.x. [DOI] [PubMed] [Google Scholar]
  5. Farrell S. O., Bieber L. L. Carnitine octanoyltransferase of mouse liver peroxisomes: properties and effect of hypolipidemic drugs. Arch Biochem Biophys. 1983 Apr 1;222(1):123–132. doi: 10.1016/0003-9861(83)90509-x. [DOI] [PubMed] [Google Scholar]
  6. Foerster E. C., Fährenkemper T., Rabe U., Graf P., Sies H. Peroxisomal fatty acid oxidation as detected by H2O2 production in intact perfused rat liver. Biochem J. 1981 Jun 15;196(3):705–712. doi: 10.1042/bj1960705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goldfischer S., Collins J., Rapin I., Coltoff-Schiller B., Chang C. H., Nigro M., Black V. H., Javitt N. B., Moser H. W., Lazarow P. B. Peroxisomal defects in neonatal-onset and X-linked adrenoleukodystrophies. Science. 1985 Jan 4;227(4682):67–70. doi: 10.1126/science.3964959. [DOI] [PubMed] [Google Scholar]
  8. Hagey L. R., Krisans S. K. Degradation of cholesterol to propionic acid by rat liver peroxisomes. Biochem Biophys Res Commun. 1982 Aug;107(3):834–841. doi: 10.1016/0006-291x(82)90598-8. [DOI] [PubMed] [Google Scholar]
  9. Hashimoto T. Individual peroxisomal beta-oxidation enzymes. Ann N Y Acad Sci. 1982;386:5–12. doi: 10.1111/j.1749-6632.1982.tb21403.x. [DOI] [PubMed] [Google Scholar]
  10. Igarashi M., Schaumburg H. H., Powers J., Kishmoto Y., Kolodny E., Suzuki K. Fatty acid abnormality in adrenoleukodystrophy. J Neurochem. 1976 Apr;26(4):851–860. doi: 10.1111/j.1471-4159.1976.tb04462.x. [DOI] [PubMed] [Google Scholar]
  11. Ikeda Y., Dabrowski C., Tanaka K. Separation and properties of five distinct acyl-CoA dehydrogenases from rat liver mitochondria. Identification of a new 2-methyl branched chain acyl-CoA dehydrogenase. J Biol Chem. 1983 Jan 25;258(2):1066–1076. [PubMed] [Google Scholar]
  12. Kase F., Björkhem I., Pedersen J. I. Formation of cholic acid from 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic acid by rat liver peroxisomes. J Lipid Res. 1983 Dec;24(12):1560–1567. [PubMed] [Google Scholar]
  13. Kawamura N., Moser H. W., Kishimoto Y. Very long chain fatty acid oxidation in rat liver. Biochem Biophys Res Commun. 1981 Apr 30;99(4):1216–1225. doi: 10.1016/0006-291x(81)90749-x. [DOI] [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Lazarow P. B., De Duve C. A fatty acyl-CoA oxidizing system in rat liver peroxisomes; enhancement by clofibrate, a hypolipidemic drug. Proc Natl Acad Sci U S A. 1976 Jun;73(6):2043–2046. doi: 10.1073/pnas.73.6.2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lazarow P. B. Rat liver peroxisomes catalyze the beta oxidation of fatty acids. J Biol Chem. 1978 Mar 10;253(5):1522–1528. [PubMed] [Google Scholar]
  17. Leighton F., Brandan E., Lazo O., Bronfman M. Subcellular fractionation studies on the organization of fatty acid oxidation by liver peroxisomes. Ann N Y Acad Sci. 1982;386:62–80. doi: 10.1111/j.1749-6632.1982.tb21408.x. [DOI] [PubMed] [Google Scholar]
  18. Leighton F., Pérsico R., Necochea C. Peroxisomal fatty acid oxidation is selectively inhibited by phenothiazines in isolated hepatocytes. Biochem Biophys Res Commun. 1984 Apr 30;120(2):505–511. doi: 10.1016/0006-291x(84)91283-x. [DOI] [PubMed] [Google Scholar]
  19. Mannaerts G. P., Debeer L. J. Mitochondrial and peroxisomal beta-oxidation of fatty acids in rat liver. Ann N Y Acad Sci. 1982;386:30–39. doi: 10.1111/j.1749-6632.1982.tb21405.x. [DOI] [PubMed] [Google Scholar]
  20. Markwell M. A., Bieber L. L., Tolbert N. E. Differential increase of hepatic peroxisomal, mitochondrial and microsomal carnitine acyltransferases in clofibrate-fed rats. Biochem Pharmacol. 1977 Sep 15;26(18):1697–1702. doi: 10.1016/0006-2952(77)90147-2. [DOI] [PubMed] [Google Scholar]
  21. Markwell M. A., Tolbert N. E., Bieber L. L. Comparison of the carnitine acyltransferase activites from rat liver peroxisomes and microsomes. Arch Biochem Biophys. 1976 Oct;176(2):497–488. doi: 10.1016/0003-9861(76)90191-0. [DOI] [PubMed] [Google Scholar]
  22. Menkes J. H., Corbo L. M. Adrenoleukodystrophy. Accumulation of cholesterol esters with very long chain fatty acids. Neurology. 1977 Oct;27(10):928–932. doi: 10.1212/wnl.27.10.928. [DOI] [PubMed] [Google Scholar]
  23. Miyazawa S., Ozasa H., Osumi T., Hashimoto T. Purification and properties of carnitine octanoyltransferase and carnitine palmitoyltransferase from rat liver. J Biochem. 1983 Aug;94(2):529–542. doi: 10.1093/oxfordjournals.jbchem.a134384. [DOI] [PubMed] [Google Scholar]
  24. Osmundsen H. Peroxisomal beta-oxidation of long fatty acids: effects of high fat diets. Ann N Y Acad Sci. 1982;386:13–29. doi: 10.1111/j.1749-6632.1982.tb21404.x. [DOI] [PubMed] [Google Scholar]
  25. Pedersen J. I., Gustafsson J. Conversion of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic acid into cholic acid by rat liver peroxisomes. FEBS Lett. 1980 Dec 1;121(2):345–348. doi: 10.1016/0014-5793(80)80377-2. [DOI] [PubMed] [Google Scholar]
  26. Powers J. M., Schaumburg H. H., Johnson A. B., Raine C. S. A correlative study of the adrenal cortex in adreno-leukodystrophy--evidence for a fatal intoxication with very long chain saturated fatty acids. Invest Cell Pathol. 1980 Oct-Dec;3(4):353–376. [PubMed] [Google Scholar]
  27. Reddy J. K., Warren J. R., Reddy M. K., Lalwani N. D. Hepatic and renal effects of peroxisome proliferators: biological implications. Ann N Y Acad Sci. 1982;386:81–110. doi: 10.1111/j.1749-6632.1982.tb21409.x. [DOI] [PubMed] [Google Scholar]
  28. Singh I., Moser A. E., Goldfischer S., Moser H. W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4203–4207. doi: 10.1073/pnas.81.13.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Singh I., Moser H. W., Moser A. B., Kishimoto Y. Adrenoleukodystrophy: impaired oxidation of long chain fatty acids in cultured skin fibroblasts an adrenal cortex. Biochem Biophys Res Commun. 1981 Oct 30;102(4):1223–1229. doi: 10.1016/s0006-291x(81)80142-8. [DOI] [PubMed] [Google Scholar]
  30. Vamecq J., Van Hoof F. Implication of a peroxisomal enzyme in the catabolism of glutaryl-CoA. Biochem J. 1984 Jul 1;221(1):203–211. doi: 10.1042/bj2210203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vamecq J., de Hoffmann E., Van Hoof F. The microsomal dicarboxylyl-CoA synthetase. Biochem J. 1985 Sep 15;230(3):683–693. doi: 10.1042/bj2300683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Van Broekhoven A., Peeters M. C., Debeer L. J., Mannaerts G. P. Subcellular distribution of coenzyme A: evidence for a separate coenzyme A pool in peroxisomes. Biochem Biophys Res Commun. 1981 May 15;100(1):305–312. doi: 10.1016/s0006-291x(81)80097-6. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES