Evaluation of neurotoxicity of porphyrinogenic agents through ALA-S, Heme oxygenase and its relationship with cytochrome p-450 levels in brain mice

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

Upsala, Suecia

Congreso; HEME OXIGENASE: REGULATION, FUNCTIONS & CLINICAL APPLICATIONS 2003 CONFERENCE; 2003

The heme oxygenase (HO) system  in animals is the first and rate-limiting step in heme degradation. In the Central Nervous System (CNS), HO pathway has been shown to act as a fundamental defensive mechanism for neurons exposed to an oxidant challenge. HO brain activity exceeds that of various systemic organs including the liver, this activity is principally attributed to the isoform HO-2. Deregulation of the HO system has been associated with the pathogenesis of several neurodegenerative disorders.                 In brain tissue, Cytochrome P-450 (CYP) was found to be mainly localized in mitochondria but only a small quantity of enzyme was also found in the microsomal fraction. Despite their relatively low content in the brain tissue, CYPs have been identified as functional enzymes, allowing CNS to metabolize a variety of substrates of both exogenous and endogenous origin.                 Drugs are mainly involved in the triggering of neurological attacks in acute porphyrias, at present, its underlying mechanism has not yet been elucidated. We have previously demonstrated that some porphyrinogenic agents altered brain cholinergic system. The aim of this work was to investigate how known porphyrinogenic drugs affect d-aminolevulinic acid synthetase (ALA-S), which is the response of HO to this challenge and which is the role of CYP in metabolizing these drugs in brain mice.                 HO activity was induced after chronic Enflurane and Isoflurane administration, griseofulvin administrated in the diet and also after starvation. Anaesthetics also provoked an increased in mRNA HO expression. The effects of drugs on ALA-S activity and mRNA expression were also discused. Mitochondrial CYP levels were 67% induced after dietary griseofulvin administration, but they were 20-40% reduced after starvation and chronic isoflurane, allylisopropilacetamide and cutaneous griseofulvin.                 Although these results indicate that the effects on brain parameters of the studied drugs differ from those reported for liver tissue and depend on the agent studied, we could suggest that HO has an important role also in the CNS.