The effect of protoporphyrinogen oxidase inhibitors on microsomal and mitochondrial cytochromes.

Abstract

Neurological dysfunction is a characteristic feature of acute porphyrias, unexplained until now. One of the possible explanations is a deficiency of heme in the central nervous system, caused by a block in porphyrin biosynthesis. To test this possibility, the content of brain mitochondrial cytochrome a3 was determined after intracerebroventricular administration of the protoporphyrinogen oxidase-inhibiting herbicide fomesafen. It was established in in vitro experiments that fomesafen is a potent inhibitor of brain mitochondrial protoporphyrinogen oxidase (PROTOOX). Addition of 10(-6) M fomesafen to incubation mixture decreased PROTOOX from 1.02 nmol/mg/h (controls) to 0.42 nmol/mg/h. 10(-5)M of fomesafen decreased this activity to 0.27 nmol/mg/h. In in vivo experiments, 5 microleters of fomesafen solution containing 0.2 M fomesafen/l was administered to male rats by intracerebroventricular injection. The content of brain mitochondrial cytochrome a3 was determined 72 hours later. A slight decrease of the a3 content was observed (control rats 0.25 nmol/mg protein, treated rats 0.22 nmol/mg). Brain cytochrome P450 activities were below detection limits in both control and treated groups. In a separate experiment, male ICR mice were fed 1000 ppm of the protoporphyrinogen oxidaseinhibiting herbicide oxadiazon in the diet for 10 days. Liver microsomal cytochrome P450 content was decreased and liver porphyrins increased. An increase of porphyrin content was also observed in the testes of oxadiazon-fed mice, but testicular cytochrome a3 content was unchanged. The results indicate that, contrary to liver microsomal cytochromes P450, the mitochondrial cytochromes are not susceptible to changes in heme biosynthesis.