Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1986 Jun 1;236(2):345–350. doi: 10.1042/bj2360345

The effect of colchicine on the development of lithocholic acid-induced cholestasis. A study of the role of microtubules in intracellular cholesterol transport.

S G Barnwell, I M Yousef, B Tuchweber
PMCID: PMC1146846  PMID: 3753453

Abstract

The pathogenesis of lithocholic acid (LCA-Na)-induced cholestasis involves a rapid accumulation of cholesterol in the bile canalicular membrane. Since microtubules play an important role in the intracellular transport of many materials, including cholesterol, the present study was undertaken to assess the extent to which they participate in the development of LCA-Na-induced cholestasis. Rats were pretreated with either colchicine (0.2 mumol/100 g body wt.) or saline solution 90 min before injection with LCA-Na (12 mumol/100 g body wt.). Colchicine, although not increasing bile flow by itself, significantly reduced the cholestasis caused by LCA-Na (57-32% reduction in bile flow) without affecting its metabolism into less toxic bile acids or its distribution in blood, liver or bile. Bile canalicular membranes isolated from animals treated with a combination of colchicine and LCA-Na contained less cholesterol than those treated with LCA-Na alone. However, membranes obtained from rats treated with colchicine alone contained much less cholesterol than did controls. It was found that the total amount of cholesterol accumulated within the bile canalicular membrane following LCA-Na treatment (LCA-Na + colchicine versus colchicine alone compared with LCA-Na versus controls) was unchanged by colchicine treatment. In view of these findings it is suggested that the total amount of cholesterol present within the bile canalicular membrane determines the extent of LCA-Na-induced cholestasis, LCA-Na probably moves cholesterol to the bile canalicular membrane via a microtubule independent pathway, and microtubules are unlikely to function in the transcellular transport of LCA-Na.

Full text

PDF
345

Selected References

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

  1. Barnwell S. G., Coleman R. Abnormal secretion of proteins into bile from colchicine-treated isolated perfused rat livers. Biochem J. 1983 Nov 15;216(2):409–414. doi: 10.1042/bj2160409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barnwell S. G., Lowe P. J., Coleman R. Effect of taurochenodeoxycholate or tauroursodeoxycholate upon biliary output of phospholipids and plasma-membrane enzymes, and the extent of cell damage, in isolated perfused rat livers. Biochem J. 1983 Oct 15;216(1):107–111. doi: 10.1042/bj2160107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barnwell S. G., Lowe P. J., Coleman R. The effects of colchicine on secretion into bile of bile salts, phospholipids, cholesterol and plasma membrane enzymes: bile salts are secreted unaccompanied by phospholipids and cholesterol. Biochem J. 1984 Jun 15;220(3):723–731. doi: 10.1042/bj2200723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonvicini F., Gautier A., Gardiol D., Borel G. A. Cholesterol in acute cholestasis induced by taurolithocholic acid. A cytochemical study in transmission and scanning electron microscopy. Lab Invest. 1978 Apr;38(4):487–495. [PubMed] [Google Scholar]
  5. Coleman R., Iqbal S., Godfrey P. P., Billington D. Membranes and bile formation. Composition of several mammalian biles and their membrane-damaging properties. Biochem J. 1979 Jan 15;178(1):201–208. doi: 10.1042/bj1780201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cooper R. A., Garcia F. A., Trey C. X. The effect of lithocholic acid on red cell membranes in vivo. J Lab Clin Med. 1972 Jan;79(1):7–18. [PubMed] [Google Scholar]
  7. Dubin M., Maurice M., Feldmann G., Erlinger S. Influence of colchicine and phalloidin on bile secretion and hepatic ultrastructure in the rat. Possible interaction between microtubules and microfilaments. Gastroenterology. 1980 Oct;79(4):646–654. [PubMed] [Google Scholar]
  8. Feldmann G., Maurice M., Sapin C., Benhamou J. P. Inhibition by colchicine of fibrinogen translocation in hepatocytes. J Cell Biol. 1975 Oct;67(1):237–243. doi: 10.1083/jcb.67.1.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. GOLDBARG J. A., RUTENBURG A. M. The colorimetric determination of leucine aminopeptidase in urine and serum of normal subjects and patients with cancer and other diseases. Cancer. 1958 Mar-Apr;11(2):283–291. doi: 10.1002/1097-0142(195803/04)11:2<283::aid-cncr2820110209>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  10. Godfrey P. P., Lembra L., Coleman R. Effects of colchicine and vinblastine on output of proteins into bile. Biochem J. 1982 Oct 15;208(1):153–157. doi: 10.1042/bj2080153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Godfrey P. P., Warner M. J., Coleman R. Enzymes and proteins in bile. Variations in output in rat cannula bile during and after depletion of the bile-salt pool. Biochem J. 1981 Apr 15;196(1):11–16. doi: 10.1042/bj1960011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goldman I. S., Jones A. L., Hradek G. T., Huling S. Hepatocyte handling of immunoglobulin A in the rat: the role of microtubules. Gastroenterology. 1983 Jul;85(1):130–140. [PubMed] [Google Scholar]
  13. Gregory D. H., Vlahcevic Z. R., Prugh M. F., Swell L. Mechanism of secretion of biliary lipids: role of a microtubular system in hepatocellular transport of biliary lipids in the rat. Gastroenterology. 1978 Jan;74(1):93–100. [PubMed] [Google Scholar]
  14. Javitt N. B. Cholestasis in rats induced by taurolithocholate. Nature. 1966 Jun 18;210(5042):1262–1263. doi: 10.1038/2101262a0. [DOI] [PubMed] [Google Scholar]
  15. Jung W., Gebhardt R., Robenek H. Primary cultures of rat hepatocytes as a model system of canalicular development, biliary secretion, and intrahepatic cholestasis. II. Taurolithocholate-induced alterations of canalicular morphology and of the distribution of filipin-cholesterol complexes. Eur J Cell Biol. 1982 Nov;29(1):77–82. [PubMed] [Google Scholar]
  16. Kakis G., Phillips M. J., Yousef I. M. The respective roles of membrane cholesterol and of sodium potassium adenosine triphosphatase in the pathogenesis of lithocholate-induced cholestasis. Lab Invest. 1980 Jul;43(1):73–81. [PubMed] [Google Scholar]
  17. Kakis G., Yousef I. M. Mechanism of cholic acid protection in lithocholate-induced intrahepatic cholestasis in rats. Gastroenterology. 1980 Jun;78(6):1402–1411. [PubMed] [Google Scholar]
  18. Kakis G., Yousef I. M. Pathogenesis of lithocholate- and taurolithocholate-induced intrahepatic cholestasis in rats. Gastroenterology. 1978 Oct;75(4):595–607. [PubMed] [Google Scholar]
  19. King J. E., Schoenfield L. J. Cholestasis induced by sodium taurolithocholate in isolated hamster liver. J Clin Invest. 1971 Nov;50(11):2305–2312. doi: 10.1172/JCI106728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Le Marchand Y., Patzelt C., Assimacopoulos-Jeannet F., Loten E. G., Jeanrenaud B. Evidence for a role of the microtubular system in the secretion of newly synthesized albumin and other proteins by the liver. J Clin Invest. 1974 Jun;53(6):1512–1517. doi: 10.1172/JCI107701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Le Marchand Y., Singh A., Assimacopoulos-Jeannet F., Orci L., Rouiller C., Jeanrenaud B. A role for the microtubular system in the release of very low density lipoproteins by perfused mouse livers. J Biol Chem. 1973 Oct 10;248(19):6862–6870. [PubMed] [Google Scholar]
  23. Lowe P. J., Barnwell S. G., Coleman R. Rapid kinetic analysis of the bile-salt-dependent secretion of phospholipid, cholesterol and a plasma-membrane enzyme into bile. Biochem J. 1984 Sep 15;222(3):631–637. doi: 10.1042/bj2220631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miyai K., Richardson A. L., Mayr W., Javitt N. B. Subcellular pathology of rat liver in cholestasis and choleresis induced by bile salts. 1. Effects of lithocholic, 3beta-hydroxy-5-cholenoic, cholic, and dehydrocholic acids. Lab Invest. 1977 Mar;36(3):249–258. [PubMed] [Google Scholar]
  25. Miyal K., Mayr W. W., Richardson A. L. Acute cholestasis induced by lithocholic acid in the rat. A freeze-fracture replica and thin section study. Lab Invest. 1975 Apr;32(4):527–535. [PubMed] [Google Scholar]
  26. Mullock B. M., Jones R. S., Peppard J., Hinton R. H. Effect of colchicine on the transfer of IgA across hepatocytes into bile in isolated perfused rat livers. FEBS Lett. 1980 Nov 3;120(2):278–282. doi: 10.1016/0014-5793(80)80316-4. [DOI] [PubMed] [Google Scholar]
  27. Orci L., Le Marchand Y., Singh A., Assimacopoulos-Jeannet F., Rouiller C., Jeanrenaud B. Letter: Role of microtubules in lipoprotein secretion by the liver. Nature. 1973 Jul 6;244(5410):30–32. doi: 10.1038/244030a0. [DOI] [PubMed] [Google Scholar]
  28. Priestly B. G., Côté M. G., Plaa G. L. Biochemical and morphological parameters of taurolithocholate-induced cholestasis. Can J Physiol Pharmacol. 1971 Dec;49(12):1078–1091. doi: 10.1139/y71-153. [DOI] [PubMed] [Google Scholar]
  29. Reaven E. P., Reaven G. M. Evidence that microtubules play a permissive role in hepatocyte very low density lipoprotein secretion. J Cell Biol. 1980 Jan;84(1):28–39. doi: 10.1083/jcb.84.1.28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Redman C. M., Banerjee D., Howell K., Palade G. E. Colchicine inhibition of plasma protein release from rat hepatocytes. J Cell Biol. 1975 Jul;66(1):42–59. doi: 10.1083/jcb.66.1.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. SCHWARTZ M. K., BODANSKY O. Glycolytic and related enzymes. Methods Med Res. 1961;9:5–23. [PubMed] [Google Scholar]
  32. Song C. S., Rubin W., Rifkind A. B., Kappas A. Plasma membranes of the rat liver. Isolation and enzymatic characterization of a fraction rich in bile canaliculi. J Cell Biol. 1969 Apr;41(1):124–132. doi: 10.1083/jcb.41.1.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Yousef I. M., Lewittes M., Tuchweber B., Roy C. C., Weber A. Lithocholic acid-cholesterol interactions in rat liver plasma membrane fractions. Biochim Biophys Acta. 1984 Dec 6;796(3):345–353. doi: 10.1016/0005-2760(84)90136-x. [DOI] [PubMed] [Google Scholar]
  34. Yousef I. M., Murray R. K. Studies on the preparation of rat liver plasma membrane fractions and on their polypeptide patterns. Can J Biochem. 1978 Jul;56(7):713–721. doi: 10.1139/o78-107. [DOI] [PubMed] [Google Scholar]
  35. Yousef I. M., Tuchweber B. Effect of lithocholic acid on cholesterol synthesis and transport in the rat liver. Biochim Biophys Acta. 1984 Dec 6;796(3):336–344. doi: 10.1016/0005-2760(84)90135-8. [DOI] [PubMed] [Google Scholar]
  36. Yousef I. M., Tuchweber B., Weber A. Prevention of lithocholate--induced cholestasis by cycloheximide, an inhibitor of protein synthesis. Life Sci. 1983 Jul 4;33(1):103–110. doi: 10.1016/0024-3205(83)90717-8. [DOI] [PubMed] [Google Scholar]

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

RESOURCES