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. 1976 Dec 1;71(3):768–780. doi: 10.1083/jcb.71.3.768

Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348

PMCID: PMC2109794  PMID: 993270

Abstract

The changes occurring in hepatocytes of F-344 male rats during a 3-wk treatment with a hypolipidemic agent, 1-methyl-4-piperidyl-bis [p- chlorophenoxy]acetate (SaH 42-348), have been evaluated by morphometric and biochemical methods. The twofold increase in liver weight resulted from a significant increase in hepatocyte cytoplasm as well as a moderate increase in the number of liver cells. The peroxisome population and SER played an overwhelming part in the hypertrophy of hepatocytic cytoplasm. The relative volume and the surface density of peroxisomes volume resulted from an increased ninefold and sevenfold, respectively. The increase in the collective peroxisome volume resulted from an increase in both the number and the average volume of peroxisomes. The SER also demonstrated a substantial increase in these values. The relative volume and surface density of mitochondria were not significantly altered in comparison to controls, while these values for RER decreased onefold. Studies on the lobular distribution of cytoplasmic organelles before and during treatment revealed that the relative volume and surface density of peroxisomes and SER increased from periportal to centrilobular cells of the hepatic lobule, whereas mitochondrial values decreased from periportal to centrilobular cells. The RER values were fairly constant in different parts of the hepatic lobule. The increase in peroxisome and SER volume and surface area was first evident within the first 3 days of SaH 42-348 treatment and these values continued to increase, reaching a steady state within 2 wk. The time course of increase in catalase and carnitine acetyltransferase activities correlated with the morphometric data on the peroxisomes. After cessation of SaH 42-348 treatment, the peroxisome values decreased rapidly within the first 3 days and reached control levels within 1 wk. Moderate reduction in SER values occurred after withdrawal of the drug, but these values remained higher than controls even after 2 wk, suggesting that the reduction in the amount of circulating peroxisome proteins may result in empty SER channels. On the 4th day of drug withdrawal a significant increase in the relative volume and surface density of lysosomes was observed, suggesting that these organelles may play some part in the removal of cellular membranes. However, the rapid reduction in peroxisome values after SaH 42-348 withdrawal appears to be due to cessation of enhanced peroxisome protein synthesis.

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Selected References

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  1. Baudhuin P., Berthet J. Electron microscopic examination of subcellular fractions. II. Quantitative analysis of the mitochondrial population isolated from rat liver. J Cell Biol. 1967 Dec;35(3):631–648. doi: 10.1083/jcb.35.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beckett R. B., Weiss R., Stitzel R. E., Cenedella R. J. Studies on the hepatomegaly caused by the hypolipidemic drugs nafenopin and clofibrate. Toxicol Appl Pharmacol. 1972 Sep;23(1):42–53. doi: 10.1016/0041-008x(72)90202-5. [DOI] [PubMed] [Google Scholar]
  3. Bolender R. P., Weibel E. R. A morphometric study of the removal of phenobarbital-induced membranes from hepatocytes after cessation of threatment. J Cell Biol. 1973 Mar;56(3):746–761. doi: 10.1083/jcb.56.3.746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bressler R., Brendel K. The role of carnitine and carnitine acyltransferase in biological acetylations and fatty acid synthesis. J Biol Chem. 1966 Sep 10;241(17):4092–4097. [PubMed] [Google Scholar]
  5. Conney A. H. Pharmacological implications of microsomal enzyme induction. Pharmacol Rev. 1967 Sep;19(3):317–366. [PubMed] [Google Scholar]
  6. Deter R. L. Quantitative characterization of dense body, autophagic vacuole, and acid phosphatase-bearing particle populations during the early phases of glucagon-induced autophagy in rat liver. J Cell Biol. 1971 Mar;48(3):473–489. doi: 10.1083/jcb.48.3.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Donaldson R. P., Tolbert N. E., Schnarrenberger C. A comparison of microbody membranes with microsomes and mitochondria from plant and animal tissue. Arch Biochem Biophys. 1972 Sep;152(1):199–215. doi: 10.1016/0003-9861(72)90208-1. [DOI] [PubMed] [Google Scholar]
  8. FRITZ I. B., SCHULTZ S. K., SRERE P. A. Properties of partially purified carnitine acetyltransferase. J Biol Chem. 1963 Jul;238:2509–2517. [PubMed] [Google Scholar]
  9. Gear A. R., Albert A. D., Bednarek J. M. The effect of the hypocholesterolemic drug clofibrate on liver mitochondrial biogenesis. A role for neutral mitochondrial proteases. J Biol Chem. 1974 Oct 25;249(20):6495–6504. [PubMed] [Google Scholar]
  10. Goldenberg H., Hüttinger M., Kampfer P., Kramar R., Pavelka M. Effect of clofibrate application on morphology and enzyme content of liver peroxisomes. Histochemistry. 1976 Feb 26;46(3):189–196. doi: 10.1007/BF02462782. [DOI] [PubMed] [Google Scholar]
  11. Hess R., Stäubli W., Riess W. Nature of the hepatomegalic effect produced by ethyl-chlorophenoxy-isobutyrate in the rat. Nature. 1965 Nov 27;208(5013):856–858. doi: 10.1038/208856a0. [DOI] [PubMed] [Google Scholar]
  12. Hruban Z., Mochizuki Y., Goto M., Slesers A., Chou S. H. Effects of some hypocholesterolemic agents on hepatic ulrastructure and microbody enzymes. Lab Invest. 1974 Apr;30(4):474–485. [PubMed] [Google Scholar]
  13. Krishnakantha T. P., Kurup C. K. Increase in hepatic catalase and glycerol phosphate dehydrogenase activities on administration of clofibrate and clofenapate to the rat. Biochem J. 1972 Nov;130(1):167–175. doi: 10.1042/bj1300167. [DOI] [PMC free article] [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. Lake B. G., Gangolli S. D., Grasso P., Lloyd A. G. Studies on the hepatic effects of orally administered di-)2-ethylhexyl) phthalate in the rat. Toxicol Appl Pharmacol. 1975 May;32(2):355–367. doi: 10.1016/0041-008x(75)90226-4. [DOI] [PubMed] [Google Scholar]
  16. Leighton F., Coloma L., Koenig C. Structure, composition, physical properties, and turnover of proliferated peroxisomes. A study of the trophic effects of Su-13437 on rat liver. J Cell Biol. 1975 Nov;67(2PT1):281–309. doi: 10.1083/jcb.67.2.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Leighton F., Poole B., Beaufay H., Baudhuin P., Coffey J. W., Fowler S., De Duve C. The large-scale separation of peroxisomes, mitochondria, and lysosomes from the livers of rats injected with triton WR-1339. Improved isolation procedures, automated analysis, biochemical and morphological properties of fractions. J Cell Biol. 1968 May;37(2):482–513. doi: 10.1083/jcb.37.2.482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Loud A. V. A quantitative stereological description of the ultrastructure of normal rat liver parenchymal cells. J Cell Biol. 1968 Apr;37(1):27–46. doi: 10.1083/jcb.37.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Markwell M. A., McGroarty E. J., Bieber L. L., Tolbert N. E. The subcellular distribution of carnitine acyltransferases in mammalian liver and kidney. A new peroxisomal enzyme. J Biol Chem. 1973 May 25;248(10):3426–3432. [PubMed] [Google Scholar]
  20. Moody D. E., Reddy J. K. Increase in hepatic carnitine acetyltransferase activity associated with peroxisomal (microbody) proliferation induced by the hypolipidemic drugs clofibrate, nafenopin, and methyl clofenapate. Res Commun Chem Pathol Pharmacol. 1974 Nov;9(3):501–510. [PubMed] [Google Scholar]
  21. Poole B., Higashi T., De Duve C. The synthesis and turnover of rat liver peroxisomes. 3. The size distribution of peroxisomes and the incorporation of new catalase. J Cell Biol. 1970 May;45(2):408–415. doi: 10.1083/jcb.45.2.408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Powanda M. C., Henriksen E. L., Ayala E., Canonico P. G. Clofibrate-induced alterations in serum protein patterns. Biochem Pharmacol. 1976 Apr 1;25(7):785–788. doi: 10.1016/0006-2952(76)90147-7. [DOI] [PubMed] [Google Scholar]
  23. Rechnagel R. O., Glende E. A., Jr Carbon tetrachloride hepatotoxicity: an example of lethal cleavage. CRC Crit Rev Toxicol. 1973 Nov;2(3):263–297. doi: 10.3109/10408447309082019. [DOI] [PubMed] [Google Scholar]
  24. Reddy J. K., Azarnoff D. L., Svoboda D. J., Prasad J. D. Nafenopin-induced hepatic microbody (peroxisome) proliferation and catalase synthesis in rats and mice. Absence of sex difference in response. J Cell Biol. 1974 May;61(2):344–358. doi: 10.1083/jcb.61.2.344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Reddy J. K. Hepatic microbody proliferation and catalase synthesis induced by methyl clofenapate, a hypolipidemic analog of CPIB. Am J Pathol. 1974 Apr;75(1):103–118. [PMC free article] [PubMed] [Google Scholar]
  26. Reddy J. K., Krishnakantha T. P., Azarnoff D. L., Moody D. E. 1-methyl-4piperidyl-bis (P-chlorophenoxy) acetate: a new hypolipidemic peroxisome proliferator. Res Commun Chem Pathol Pharmacol. 1975 Mar;10(3):589–592. [PubMed] [Google Scholar]
  27. Reddy J. K., Krishnakantha T. P. Hepatic peroxisome proliferation: induction by two novel compounds structurally unrelated to clofibrate. Science. 1975 Nov 21;190(4216):787–789. doi: 10.1126/science.1198095. [DOI] [PubMed] [Google Scholar]
  28. Reddy J. K., Moody D. E., Azarnoff D. L., Rao M. S. Di-(2-ethylhexyl)phthalate: an industrial plasticizer induces hypolipidemia and enhances hepatic catalase and carnitine acetyltransferase activities in rat and mice. Life Sci. 1976 May 1;18(9):941–945. doi: 10.1016/0024-3205(76)90412-4. [DOI] [PubMed] [Google Scholar]
  29. Reddy J., Svoboda D. Further evidence to suggest that microbodies do not exist as individual entities. Am J Pathol. 1973 Mar;70(3):421–438. [PMC free article] [PubMed] [Google Scholar]
  30. Salvador R. A., Haber S., Atkins C., Gommi B. W., Welch R. M. Effect of clofibrate and 1-methyl-4-piperidyl bis (p-chlorophenoxy) acetate (Sandox 42-348) on steroid and drug metabolism by rat liver microsomes. Life Sci. 1970 Apr 8;9(7):397–407. doi: 10.1016/0024-3205(70)90242-0. [DOI] [PubMed] [Google Scholar]
  31. Schulte-Hermann R. Induction of liver growth by xenobiotic compounds and other stimuli. CRC Crit Rev Toxicol. 1974 Sep;3(1):97–158. doi: 10.3109/10408447409079856. [DOI] [PubMed] [Google Scholar]
  32. Solberg H. E. Different carnitine acyltransferases in calf liver. Biochim Biophys Acta. 1972 Nov 30;280(3):422–433. doi: 10.1016/0005-2760(72)90248-2. [DOI] [PubMed] [Google Scholar]
  33. Stäubli W., Hess R., Weibel E. R. Correlated morphometric and biochemical studies on the liver cell. II. Effects of phenobarbital on rat hepatocytes. J Cell Biol. 1969 Jul;42(1):92–112. doi: 10.1083/jcb.42.1.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Svoboda D., Grady H., Azarnoff D. Microbodies in experimentally altered cells. J Cell Biol. 1967 Oct;35(1):127–152. doi: 10.1083/jcb.35.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Timms A. R., Kelly L. A., Ho R. S., Trapold J. H. Laboratory studies of 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH 42-348)--a new hypolipidemic agent. Biochem Pharmacol. 1969 Aug;18(8):1861–1871. doi: 10.1016/0006-2952(69)90281-0. [DOI] [PubMed] [Google Scholar]
  36. Weibel E. R., Kistler G. S., Scherle W. F. Practical stereological methods for morphometric cytology. J Cell Biol. 1966 Jul;30(1):23–38. doi: 10.1083/jcb.30.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Weibel E. R., Stäubli W., Gnägi H. R., Hess F. A. Correlated morphometric and biochemical studies on the liver cell. I. Morphometric model, stereologic methods, and normal morphometric data for rat liver. J Cell Biol. 1969 Jul;42(1):68–91. doi: 10.1083/jcb.42.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]

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