Oxidative injury mediated by the hepatic cytochrome P-450 system in conjunction with cellular iron. Effects on the pathway of haem biosynthesis.
1. Some polyhalogenated aromatic chemicals such as 2,3,7,8-tetrachloro-p-dioxin, brominated and chlorinated biphenyls, and hexachlorobenzene cause in humans, animals and hepatocyte systems a partial block in haem biosynthesis leading to accumulation and excretion of uroporphyrin, the oxidation product of the unstable biosynthetic intermediate uroporphyrinogen. 2. The involvement of reactive toxic metabolites of the halogenated chemicals has previously been suggested. The evidence presented in this paper supports a different mechanism involving chronic induction of the microsomal cytochrome P-450 system, mobilization of hepatocellular iron and associated oxidative stress. Besides oxidation of uroporphyrinogen to uroporphyrin, an inhibitor of uroporphyrinogen decarboxylase may also be formed. 3. Studies with iron-loaded mice and chicken embryo hepatocytes show that under appropriate conditions iron alone, or chemicals such as beta-naphthoflavone which induce the same cytochromes P-450 isozymes as do the chlorinated aromatics, will cause a similar uroporphyria. These findings provide an experimental model for the human disease porphyria cutanea tarda, sometimes occurring in patients with liver damage. 4. Experiments with rats and iron-loaded mice indicate that there may also be an association between the induction of uroporphyria and the development of liver tumours after administration of polyhalogenated aromatic chemicals.