Inducing coproporphyria in rat hepatocyte cultures using cyclic AMP and cyclic AMP-releasing agents.
Cyclic AMP (c-AMP), added on its own to rat hepatocyte cultures, caused a marked accumulation of coproporphyrin III. The results obtained by comparing the effect of c-AMP to that of exogenous 5-aminolevulinate (ALA), and from adding c-AMP and ALA together, indicated that the coproporphyrinogen III metabolism was blocked, even though no inhibition of the relevant enzyme, coproporphyrinogen oxidase, could be demonstrated. Preferential accumulation of coproporphyrin could also be produced in cultures of rat hepatocytes by agents that raise the cellular levels of cyclic AMP, such as glucagon. The effect of supplementing the culture medium with triiodothyronine (T3) on the response of rat hepatocytes to c-AMP was also investigated. T3, which is known to stimulate mitochondrial respiration, uncoupling O2 consumption from ATP synthesis, produced a c-AMP-like effect when given on its own and potentiated the effect of c-AMP, with an apparent increase in the severity of the metabolic block. It is suggested that an oxidative mechanism may be activated in c-AMP and T3-induced coproporphyria, preferentially involving the mitochondrial compartment, leading to oxidation of porphyrinogen intermediates of haem biosynthesis, especially coproporphyrinogen. Coproporphyin, the fully oxidized aromatic derivative produced, cannot be metabolized and will therefore accumulate.
De Matteis
Francesco
F
Medical Research Council Bioanalytical Group, School of Biological and Chemical Sciences, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK. fandjdem@waitrose.com
Harvey
Carolyn
C
D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003304:Coproporphyrinogen Oxidase / Q000378:metabolism; D003306:Coproporphyrins / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011164:Porphyrias / Q000139:chemically induced*; D011524:Protoporphyrins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014284:Triiodothyronine / Q000494:pharmacology
D003306:Coproporphyrins; D011524:Protoporphyrins; D014284:Triiodothyronine; C026971:coproporphyrin III; D000622:Aminolevulinic Acid; D005934:Glucagon; D000242:Cyclic AMP; D003304:Coproporphyrinogen Oxidase; D007545:Isoproterenol