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International Journal of Experimental Pathology logoLink to International Journal of Experimental Pathology
. 1992 Oct;73(5):665–673.

Protoporphyrin overload in unrestrained rats: biochemical and histopathologic characterization of a new model of protoporphyric hepatopathy.

M M Berenson 1, R Kimura 1, W Samowitz 1, D Bjorkman 1
PMCID: PMC2002016  PMID: 1419780

Abstract

We determined the feasibility of producing protoporphyric hepatopathy in unrestrained rats by infusing protoporphyrin into their portal circulation via chronic indwelling catheters. Sprague-Dawley rats, 200-300 g, received single (8.5-27.8 mumol) or multiple (64.1-208.7 mumol) infusions of protoporphyrin over 3-240 h. Single protoporphyrin infusions increased the hepatic protoporphyrin concentration from < 1 nmol/g up to 1368 nmol/g; multiple infusions up to 3908 nmol/g. The maximal non-hepatic tissue concentrations averaged 243 nmol/g in the spleen. Hepatocanalicular and ductular birefringent pigmented deposits were found in all livers, generally proportional to the protoporphyrin load. Aggregates of crystalline protoporphyrin were detected in biliary ductules, canaliculi, hepatocytes, Kupffer cells and fat-storage cells by electron microscopy. Laboratory abnormalities included elevations of the transaminases, LDH, GGTP and bilirubin and a modest fall in the haematocrit suggesting a mixture of red blood cell and hepatic injury. Thus, protoporphyric hepatopathy was produced by infusions of protoporphyrin into the portal circulation. This model may aid in understanding the pathogenesis and pathophysiology of liver disease in protoporphyria.

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Selected References

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  1. Avner D. L., Lee R. G., Berenson M. M. Protoporphyrin-induced cholestasis in the isolated in situ perfused rat liver. J Clin Invest. 1981 Feb;67(2):385–394. doi: 10.1172/JCI110046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berenson M. M., Gunther C., Samowitz W. S., Bjorkman D. J. Formation of biliary thrombi in protoporphyrin-induced cholestasis in perfused rat liver. Hepatology. 1990 May;11(5):757–763. doi: 10.1002/hep.1840110508. [DOI] [PubMed] [Google Scholar]
  3. Bloomer J. R., Enriquez R. Evidence that hepatic crystalline deposits in a patient with protoporphyria are composed of protoporphyrin. Gastroenterology. 1982 Mar;82(3):569–573. [PubMed] [Google Scholar]
  4. Bloomer J. R., Phillips M. J., Davidson D. L., Klatskin G., Bloomer Hepatic disease in erythropoietic protoporphyria. Am J Med. 1975 Jun;58(6):869–882. doi: 10.1016/0002-9343(75)90644-0. [DOI] [PubMed] [Google Scholar]
  5. Bonkowsky H. L., Bloomer J. R., Ebert P. S., Mahoney M. J. Heme synthetase deficiency in human protoporphyria. Demonstration of the defect in liver and cultured skin fibroblasts. J Clin Invest. 1975 Nov;56(5):1139–1148. doi: 10.1172/JCI108189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gschnait F., Konrad K., Hönigsmann H., Denk H., Wolff K. Mouse model for protoporphyria. I. The liver and hepatic protoporphyrin crystals. J Invest Dermatol. 1975 Sep;65(3):290–299. doi: 10.1111/1523-1747.ep12598357. [DOI] [PubMed] [Google Scholar]
  7. Klatskin G., Bloomer J. R. Birefringence of hepatic pigment deposits in erythropoietic protoporphyria. Specificity of polarization microscopy in the identification of hepatic protoporphyrin deposits. Gastroenterology. 1974 Aug;67(2):294–302. [PubMed] [Google Scholar]
  8. Koller M. E., Romslo I. Studies on the uptake of porphyrin by isolated rat liver mitochondria. Biochim Biophys Acta. 1978 Aug 8;503(2):238–250. doi: 10.1016/0005-2728(78)90185-8. [DOI] [PubMed] [Google Scholar]
  9. Kools A. M., Straka J. G., Hill H. D., Whitmer D. I., Holman R. T., Bloomer J. R. Modulation of hepatic ferrochelatase activity by dietary manipulation of mitochondrial phospholipid fatty acyl groups. Hepatology. 1989 Apr;9(4):557–561. doi: 10.1002/hep.1840090409. [DOI] [PubMed] [Google Scholar]
  10. Lefkowitch J. H., Feng-Chen K. C., Sklar J. A., Poh-Fitzpatrick M. B. Cholic acid amelioration of light and electron microscopic hepatic lesions in experimental protoporphyria. Hepatology. 1983 May-Jun;3(3):399–406. doi: 10.1002/hep.1840030319. [DOI] [PubMed] [Google Scholar]
  11. Nakao K., Wada O., Takaku F., Sassa S., Yano Y., Urata G. The origin of the increased protoporphyrin in erythrocytes of mice with experimentally induced porphyria. J Lab Clin Med. 1967 Dec;70(6):923–932. [PubMed] [Google Scholar]
  12. Piomelli S. A micromethod for free erythrocyte porphyrins: the FEP test. J Lab Clin Med. 1973 Jun;81(6):932–940. [PubMed] [Google Scholar]
  13. Rademakers L. H., Cleton M. I., Kooijman C., Baart de la Faille H., van Hattum J. Early involvement of hepatic parenchymal cells in erythrohepatic protoporphyria? An ultrastructural study of patients with and without overt liver disease and the effect of chenodeoxycholic acid treatment. Hepatology. 1990 Mar;11(3):449–457. doi: 10.1002/hep.1840110316. [DOI] [PubMed] [Google Scholar]
  14. Van Steveninck J., Boegheim J. P., Dubbelman T. M., Van der Zee J. The influence of porphyrins on iron-catalysed generation of hydroxyl radicals. Biochem J. 1988 Feb 15;250(1):197–201. doi: 10.1042/bj2500197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. White I. N., White J. A., Liem H. H., Muller-Eberhard U. Decreased cytochrome P450 and increased prophyrin concentrations in the livers of rats on a low iron diet given a single dose of desferrioxamine. Biochem Pharmacol. 1978 Mar 15;27(6):865–870. doi: 10.1016/0006-2952(78)90410-0. [DOI] [PubMed] [Google Scholar]

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