Skip to main content
SpringerLink
Log in

Plasma high-density lipoproteins and hepatic microsomal enzyme induction

Relation to histological changes in the liver

  • Originals
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Summary

The relationship between high-density lipoproteins (HDL) in plasma and hepatic structure and microsomal function has been investigated in 54 patients undergoing diagnostic liver biopsy. Plasma HDL cholesterol and major apoproteins were correlated with hepatic histology and microsomal enzyme activity assessed directly as liver cytochrome P-450 concentration and indirectly by plasma antipyrine clearance rate. HDL cholesterol, the concentrations of apoproteins A-I and A-II, the HDL cholesterol/total cholesterol ratio and cytochrome P-450 were low in subjects with moderate or severe hepatic fatty infiltration or cirrhosis when compared with the values for subjects with a normal liver. HDL cholesterol and apoprotein A-I and the HDL cholesterol/total cholesterol ratio were directly proportional to the amount of non-fatty parenchyma in the livers. Subjects with a normal liver undergoing treatment with enzyme-inducing drugs, such as phenytoin, phenobarbital and primidone, had higher HDL cholesterol, apoproteins A-I and A-II, HDL cholesterol/total cholesterol ratio, cytochrome P-450 and antipyrine clearance rate than subjects not receiving such therapy. Treatment with inducers appeared to have compensated for the effect of liver disease in lowering plasma HDL. In the entire population, and also in subjects not taking inducing drugs, when considered separately, plasma HDL cholesterol, apoproteins A-I and A-II and the HDL cholesterol/total cholesterol ratio were significantly correlated with cytochrome P-450 concentration. In subjects on enzyme inducers, HDL cholesterol and apoprotein A-I levels and the HDL cholesterol/total cholesterol ratio were proportional to the magnitude of the induction. Serum triglycerides were inversely proportional to the measures of liver microsomal enzyme activity. The lipoprotein pattern, high HDL cholesterol and apoproteins A-I and A-II, and high HDL cholesterol/total cholesterol ratio that accompany microsomal induction are characterized by a reduced risk of atherosclerotic vascular disease and a prolonged expectation of life. The plasma changes presumably reflect the effect of enzyme inducers, such as phenytoin and phenobarbital on hepatic lipids and proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Andreasen PB, Ranek L, Statland BE, Tygstrup N (1974) Clearance of antipyrine — dependence of quantitative liver function. Eur J Clin Invest 4: 129–134

    Google Scholar 

  2. Avogaro P, Bittolo Bon G, Gazzolato G, Quinci GB (1979) Are apolipoproteins better discriminators than lipids for atherosclerosis? Lancet 1: 901–903

    Google Scholar 

  3. Van Berkel TJC, Koster JF, Hülsmann WC (1977) High density lipoprotein and low density lipoprotein catabolism by human liver and parenchymal and non-parenchymal cells from rat liver. Biochim Biophys Acta 486: 586–589

    Google Scholar 

  4. Branch RA, Herbert CM, Read AE (1973) Determinants of serum antipyrine half-lives in patients with liver disease. Gut 14: 569–573

    Google Scholar 

  5. Brodie BB, Axelrod J (1950) The fate of antipyrine in man. J pharmacol Exp Ther 98: 97–104

    Google Scholar 

  6. Carlson LA, Kolmodin-Hedman B (1972) Hyper-α-lipoproteinemia in men exposed to chlorinated hydrocarbon pesticides. Acta Med Scand 192: 29–32

    Google Scholar 

  7. Cheung MC, Albers JJ (1977) The measurement of apolipoprotein A-I and A-II levels in man and women by immunoassay. J Clin Invest 60: 43–50

    Google Scholar 

  8. Conney AH (1967) Pharmacological implications of enzyme induction. Pharmacol Rev 19: 317–366

    Google Scholar 

  9. Davidson DC, McIntosh WB, Ford JA (1974) Assessment of plasma γ-glutamyltranspeptidase activity and D-Glucaric acid excretion as indices of enzyme induction. Clin Sci Mol Med 47: 279–283

    Google Scholar 

  10. Eisenberg S, Levy RI (1975) Lipoproteins and lipoprotein metabolism, In: Kritchevsky D (ed) Hypolipidemic agents. Springer, Berlin Heidelberg New York, pp 191–208

    Google Scholar 

  11. Gillette JR (1975) Other aspects of pharmacokinetics. In: Gillette JR, Mitchell JR (eds) Handbook of experimental pharmacology, Vol. 28 (3). Springer, Berlin Heidelberg New York, pp 35–85

    Google Scholar 

  12. Glickman RM, Green PHR, Lees RS, Tall A (1978) Apoprotein A-I synthesis in normal intestinal mucosa and in Tangier disease. N Engl J Med 299: 1424–1427

    Google Scholar 

  13. Glomset JA (1968) Physiological role of lecithin cholesterol acultransferase. Am J Clin Nutr 23: 1129–1136

    Google Scholar 

  14. Glueck CJ, Fallat RW, Millett F, Gartside P, Elston RC, Go RCP (1975) Familiar hyper-alpha-lipoproteinemia. Studies in eighteen kindreds. Metabolism 24: 1243–1265

    Google Scholar 

  15. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR (1977) High-density lipoprotein as a protective factor against coronary heart disease. The Framingham study. Am J Med 62: 707–714

    Google Scholar 

  16. Greim H, Schenkman M, Klotzbucher M, Remmer H (1970) The influence of phenobarbital on the turnover of hepatic microsomal cytochrome b5 and cytochrome P-450 in the rat. Biochim Biophys Acta 201: 20–25

    Google Scholar 

  17. Hamilton RL, Williams MC, Fielding CJ, Havel RJ (1976) Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver. J Clin Invest 58: 667–680

    Google Scholar 

  18. Hunter J, Carerella M, Maxwell JD, Stewart DA, Williams R (1971) Urinary D-glucaric acid excretion as a test for hepatic enzyme induction in man. Lancet 1: 572–575

    Google Scholar 

  19. Huttunen JK, Länsimies E, Voutilainen E, Ehnholm C, Hietanen E, Penttilä I, Siitonen O, Rauramaa R (1979) Effect of moderate physical exercise on serum lipoproteins. Circulation 60: 1220–1229

    Google Scholar 

  20. Ishikawa TT, Stewart LE, Brazier JB, Steiner PM, Gartside PS, Glueck CJ (1976) A study of the heparin-manganese chloride method for determination of plasma α-lipoprotein cholesterol concentration. Lipids 11: 628–633

    Google Scholar 

  21. Jackson LR, Morrisett JD, Gotto AM Jr (1976) Lipoprotein structure and metabolism. Physiol Rev 56: 259–316

    Google Scholar 

  22. Johansson BJ, Medhus A (1974) Increase in plasma α-lipoproteins in chronic-alcoholics after acute abuse. Acta Med Scand 195: 273–277

    Google Scholar 

  23. Luoma PV, Ehnholm C, Pelkonen RO, Sotaniemi EA (1979) Correlation of plasma high-density lipoprotein cholesterol and apolipoproteins A-I and A-II to hepatic microsomal activity in man (Abstract). In: Kalliomäki JL, Viikari J, Lehtonen A, Rönnemaa T (eds) Proceedings of the Third Scandinavian Symposium on Atherosclerosis Research, Turku, Aug 31–Sept 1, 1979. Pika Company Ltd, Turku, Finland, p 40

    Google Scholar 

  24. Luoma PV, Pelkonen RO, Myllylä V, Sotaniemi EA (1979) Relationship between serum lipid levels and indices of drug metabolism in epileptics on anticonvulsants (Abstract). Clin Pharmacol Ther 25: 235

    Google Scholar 

  25. Luoma PV, Sotaniemi EA, Ehnholm C (1980) Low high-density lipoprotein and reduced antipyrine metabolism in members of a family with polycystic liver disease. Scand J Gastroenterol 15: 869–873

    Google Scholar 

  26. Lux SE, Hirz R, Shrager RI, Gotto AM Jr (1972) The influence of lipid on the conformation of human plasma high density apolipoproteins. J Biol Chem 247: 2598–2606

    Google Scholar 

  27. Marsh CA (1963) Metabolism of D-glucurolactone in mammalian systems. Biochem J 86: 77–86

    Google Scholar 

  28. Miller GJ, Miller NE (1975) Plasma high-density lipoprotein concentration and development of ischaemic heart disease. Lancet 1: 16–19

    Google Scholar 

  29. Miller NE, Weinstein DB, Steinberg D (1977) Binding, internalization and degradation of high-density lipoprotein by cultured normal human fibroblasts. J Lipid Res 18: 438–450

    Google Scholar 

  30. Nakaya N, Hong Chung B, Taunton OD (1977) Synthesis of plasma lipoproteins by the isolated perfused liver from the fasted and fed pig. J Biol Chem 252: 5258–5261

    Google Scholar 

  31. Nikkilä EA (1978) Metabolic regulation of plasma high-density lipoprotein concentrations. Eur J Clin Invest 8: 111–113

    Google Scholar 

  32. Nikkilä EA, Kaste M, Ehnholm C, Viikari J (1978) Increase in serum high-density lipoproteins in phenytoin users. Br Med J 2: 99

    Google Scholar 

  33. Ohnhaus EE, Kirchof B, Peheim E (1979) Effect of enzyme induction on plasma lipids using antipyrine, phenobarbital, and rifampicin. Clin Pharmacol Ther 25: 591–597

    Google Scholar 

  34. Papadopoulos NM, Charles MA (1970) Serum lipoprotein patterns in liver disease. Proc Soc Exp Biol Med 134: 797–799

    Google Scholar 

  35. Prescott LF, Adjepon-Yamoak KK, Roberts E (1973) Rapid gas-liquid chromatographic estimation of antipyrine in plasma. J Pharm Pharmacol 25: 205–207

    Google Scholar 

  36. Rachmilewitz D, Fainary M (1979) Apolipoprotein A-I synthesis and secretion by cultured human intestinal mucosa. Metabolism 28: 739–743

    Google Scholar 

  37. Remmer H, Bock KW (1974) The role of the liver in drug metabolism. In: Schaffner F, Sherlock S, Leevy CM (eds) The liver and its diseases. Georg Thieme, Stuttgart, pp 34–42

    Google Scholar 

  38. Roots I, Saalfrank K, Hildebrandt AG (1975) Comparison of methods to study enzyme induction in man. Adv Exp Med Biol 58: 485–502

    Google Scholar 

  39. Rubin E, Hutterer F, Lieber CS (1968) Ethanol increases hepatic smooth endoplasmic reticulum and drug metabolizing enzymes. Science 162: 1469–1470

    Google Scholar 

  40. Russell RL, Soler-Argilaga C, Heimberg M (1976) Stimulation of serum lecithin-cholesterol acyltransferase activity by phenobarbital in the rat. Life Sci 19: 1347–1350

    Google Scholar 

  41. Rössner S, Kjellin KG, Mettinger KL, Siden Å, Söderström CE (1978) Normal serum cholesterol, but low H.D.L. cholesterol concentration in young patients with ischaemic cerebrovascular disease. Lancet 1: 577–579

    Google Scholar 

  42. Sabesin SM, Hawkins HL, Kuken L, Ragland JB (1977) Abnormal plasma lipoproteins and lecithin-cholesterol acyltransferase deficiency in alcoholic liver disease. Gastroenterology 72: 510–518

    Google Scholar 

  43. Schoene B, Fleishman RA, Remmer H, Olderhausen HF (1972) Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J Clin Pharmacol 4: 65–73

    Google Scholar 

  44. Sigurdsson G, Noel SP, Havel RJ (1979) Quantification of the hepatic contribution of the catabolism of high density lipoproteins in rats. J Lipid Res 20: 316–324

    Google Scholar 

  45. Sotaniemi EA, Ahlquist J, Pelkonen RO, Pirttiaho H, Luoma PV (1977) Histological changes in the liver and the indices of drug metabolism in alcoholics. Eur J Clin Pharmacol 11: 295–303

    Google Scholar 

  46. Sotaniemi EA, Medzihradsky F, Eliasson G (1974) Glucaric acid as an indicator of use of enzyme-inducing drugs. Clin Pharmacol Ther 19: 417–423

    Google Scholar 

  47. Sotaniemi EA, Pelkonen RO, Ahokas JT, Pirttiaho HI, Ahlquist J (1978) Drug metabolism in epileptics: In vivo - in vitro correlations. Br J Clin Pharmacol 5: 71–76

    Google Scholar 

  48. Sotaniemi EA, Pelkonen RO, Ahokas JT, Pirttiaho HI, Ahlquist J (1978) Relationship between in vivo and in vitro drug metabolism in man. Eur J Drug Metab Pharmakokinet 3: 39–45

    Google Scholar 

  49. Sotaniemi EA, Pelkonen RO, Puukka M (1980) Measurement of hepatic drug-metabolizing enzyme activity in man — comparison of three different assays. Eur J Clin Pharmacol 17: 267–274

    Google Scholar 

  50. Stein O, Stein Y (1975) Surface binding and interiorization of homologous and heterologous serum lipoproteins by rat aortic smooth muscle cells in culture. Biochim Biophys Acta 398: 377–385

    Google Scholar 

  51. Van Tol A, van Gent T, van't Hooft FM, Vlaspolder F (1978) High density lipoprotein catabolism before and after partial hepatectomy. Atherosclerosis 29: 439–448

    Google Scholar 

  52. Torsvik H, Solaas MH, Gjone E, (1970) Serum lipoproteins in plasma in lecithin-cholesterol acyltransferase deficiency studied by electronmicroscopy. Clin Genet 1: 139–150

    Google Scholar 

  53. Vesell ES (1979) The antipyrine test in clinical pharmacology: conceptions and misconceptions. Clin Pharmacol Ther 26: 275–286

    Google Scholar 

  54. Weibel ER, Stäubli W, Gnägi HR, Hess FA (1969) Correlated morphometric and biochemical studies on the liver cell. I Morphometric model, stereological methods, and normal morphometric data for rat liver. J Cell Biol 42: 68–91

    Google Scholar 

  55. Wilkinson GR, Schenker S (1976) Effects of liver disease on drug disposition in man. Biochem Pharmacol 25: 2675–2681

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Research Unit, Department of Internal Medicine, University of Oulu, Oulu, Finland

    P. V. Luoma & E. A. Sotaniemi

  2. Department of Pharmacology, University of Oulu, Oulu, Finland

    R. O. Pelkonen

  3. Department of Pathology, University of Oulu, Oulu, Finland

    A. Arranto

  4. Central Public Health Laboratory, Helsinki, Finland

    C. Ehnholm

Authors
  1. P. V. Luoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. A. Sotaniemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. O. Pelkonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Arranto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Ehnholm
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luoma, P.V., Sotaniemi, E.A., Pelkonen, R.O. et al. Plasma high-density lipoproteins and hepatic microsomal enzyme induction. Eur J Clin Pharmacol 23, 275–282 (1982). https://doi.org/10.1007/BF00547568

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00547568

Key words

Search

Navigation