Archives of Toxicology

, Volume 66, Issue 3, pp 175–181

Inhibition of ferrochelatase and accumulation of porphyrins in mouse hepatocyte cultures exposed to porphyrinogenic chemicals

  • Angela M. Brady
  • Edward A. Lock
Original Investigations

DOI: 10.1007/BF01974011

Cite this article as:
Brady, A.M. & Lock, E.A. Arch Toxicol (1992) 66: 175. doi:10.1007/BF01974011

Abstract

The ability of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (EDDC) and griseofulvin to induce porphyria in primary cultures of mouse hepatocytes has been examined. Exposure of cultured mouse hepatocytes to DDC, EDDC or griseofulvin resulted in a marked inhibition of ferrochelatase which was sustained over the 4-day exposure period. Maximal concentrations of DDC (25 μM), EDDC (25 μM) and griseofulvin (25 μM) resulted in 14-fold, 30-fold and 9-fold increases, respectively, in total porphyrin in the culture medium. Analysis of the porphyrins accumulating indicated a predominance of protoporphyrin with all three xenobiotics. Addition of 5-aminolaevulinic acid (ALA) to mouse hepatocyte cultures (10–1000 μM) resulted in much larger increases (up to 164-fold) in porphyrin accumulation in the medium and the porphyrin accumulating was predominantly uroporphyrin. These studies have demonstrated that primary cultures of mouse hepatocytes provide a valid mechanism-based in vitro model of the hepatic porphyrias produced by the dihydropyridines and griseofulvin in mice.

Key words

Porphyria Hepatocyte cultures Dihydropyridines Griseofulvin Ferrochelatase 

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Angela M. Brady
    • 1
  • Edward A. Lock
    • 1
  1. 1.Biochemical Toxicology Section, Imperial Chemical Industries PLCCentral Toxicology LaboratoryMacclesfieldUK

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