Inhibition of ferrochelatase and accumulation of porphyrins in mouse hepatocyte cultures exposed to porphyrinogenic chemicals.
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 microM), EDDC (25 microM) and griseofulvin (25 microM) 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 microM) 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.
Brady
A M
AM
Biochemical Toxicology Section, Imperial Chemical Industries PLC, Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Lock
E A
EA
D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000633:toxicity; D005294:Ferrochelatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006118:Griseofulvin / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008107:Liver Diseases / Q000201:enzymology; D008297:Male; D051379:Mice; D011164:Porphyrias / Q000139:chemically induced / Q000201:enzymology; D011166:Porphyrins / Q000493:pharmacokinetics / Q000633:toxicity*
D011166:Porphyrins; C030826:3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine; D006118:Griseofulvin; D003997:Dicarbethoxydihydrocollidine; D000622:Aminolevulinic Acid; D005294:Ferrochelatase