Evaluation of neurotoxicity of porphyrinogenic agents through different biochemical parameters related to heme metabolism

RODRÍGUEZ, JORGE; LAVANDERA, JIMENA; MARTÍNEZ, MARIA DEL CARMEN; GEREZ, ESTHER; BATLLE, ALCIRA; BUZALEH, ANA MARIA

Praga, República Checa

Congreso; Porphyrins and Porphyrias 2003; 2003

European Porphyria Association

Several drugs are mainly envolved in the triggering of neurological attacks in acute porphyrias, however, the neurological mechanism envolved has not been yet elucidated. We have previously demostrated that some porphyrinogenic agents altered brain cholinergic system. Heme oxygenase (HO), the rate-limiting step in heme degradation exists in three isoforms HO-1, HO-2 and HO-3. Brain HO activity exceeds that of various systemic organs including liver, this activity is largely attributed to HO-2. Cytochrome P-450 (CYP) was found to be mainly localized in mitochondria but only a small quantity of the enzyme was also found in the microsomal fraction. Despite their relatively low content in the brain tissue, cytochrome P450 have been  identified as functinal enzymes, allowing central nervous system to metabolize a variety of substrates of both exogenous and endogenous origin. The aim of this work was to investigate how know porphyrinogenic drugs affect ä-aminolevulinic acid synthetase (ALA-S) and HO and which is the role of CYP in metabolizing these drugs in brain mice. ALA-S activity was more than 100% induced after anaesthetic, veronal and ethanol administration. HO activity was increased after chronic Enflurane and Isoflurane administration, dietary griseofulvin and after starvation ALA-S and HO gene expression were also evaluated. Mitochondrial CYP levels were 67% induced after dietary griseofulvin, but it was 20-40% reduced after starvation and chronic isoflurane, allylisopropylacetamide and cutaneous griseofulvin application. Data indicate that the effects of the drugs studied on brain parameters differ from those reported for liver tissue and depend on the agent examined.