CONICET | Buscador de Institutos y Recursos Humanos

The pathophysiology of acute attacks of porphyrias could be related to the toxic effects of porphyrins or their precursors on Central Nervous System or to low levels of heme as a cofactor for nitric oxide synthase (NOS), the enzyme responsible for producing NO. Drugs are mainly involved in the triggering of porphyrias and d-aminolevulinic acid (ALA) accumulation contributes to their neurological manifestations. Moreover, ALA inhibits glutamate uptake, affecting the glutamatergic neurotransmission. The aim of this work was to investigate how known porphyrinogenic agents affect nitric oxide metabolism. To this end the activity of NOS was measured in the cytosolic and mitochondrial subcellular fractions of liver and brain of mice. NOS activity varied depending on the porphyrinogenic agent assayed. Chronic Enflurane and Isoflurane administration increased cytosolic NOS activity in liver and the mitochondrial enzyme in brain. Ethanol caused a 37% (p<0.05) increase of brain mitochondrial NOS activity, without any change in the cytosolic form or in liver. Oral griseofulvin only produced a 55% (p<0.05) induction in the liver mitochondrial enzyme. On the contrary, when ALA was chronically administered to mice a reduction between 30-50% (p<0.05) in liver NOS activity was detected; ALA also caused a diminution of 26% (p<0.05) in brain cytosolic enzyme activity. The action of porphyrinogenic agents on N-methyl-D-aspartate (NMDA) receptor levels was also investigated. NMDA receptor levels were 40% increased in cerebellum of mice treated with ethanol. Oral griseofulvin caused no alterations. Our present and previously results indicate that porphyrinogenic agents would have a widespread action in brain affecting several metabolisms, which could be the reason for the difficult to establish the onset of the neurological manifestations of the porphyrias.

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