CYP2E1 in brain: A hemeprotein involved in the metabolization of volatile anaesthetics and ethanol in both microsomes and mitochondria

LAVANDERA, JIMENA; BATLLE, ALCIRA; BUZALEH, ANA MARIA

Rotterdam

Congreso; Porphyrins and Porphyrias - Rotterdam 2007; 2007

University Medical Center Rotterdam-Erasmus MC

Brain cytochrome P-450 (CYP) metabolizes a variety of compounds, including many drugs that cross the blood-barrier to produce their pharmacological effects within the brain. The effect of known porphyrinogenic drugs in brain mice has been studied in our laboratory. Porphyrinogenic agents affected cholinergic system and heme metabolism; induced oxidative stress and altered mitochondrial CYP levels. In particular, Isoflurane, a volatile anaesthetic and starvation diminished mitochondrial CYP content, without alterating its microsomal levels; while ethanol caused no changes. So, it was of interest to determine if these findings were the result of a direct effect on the isoform CYP2E1 in brain or indirectly due to alterations on the activity and the expression of 5-aminolevulic acid synthetase and heme oxygenase as we have previously reported. The aim of this work was to evaluate any alteration in the activity and/or the expression of CYP2E1 isoform in mice receiving Enflurane and Isoflurane anaesthetics, ethanol or starved for 24 hours. To this end, CYP2E1 activity was measured and Western Blots were performed in microsomes and mitochondria of encephalon. CYP2E1 mitochondrial activity was induced more than 200% (p<0.01) by acute anaeshesia with Enflurane and in animals under starvation; while the activity of microsomal protein was enhanced (220%, p<0.01) in alcoholized animals. A concomitant increase in protein expression was observed by effect of ethanol in microsomes. Isoflurane provoked opposite effects on CYP2E1 expression in mitochondria and microsomes. Results here presented indicate that CYP2E1, alike in liver, would participate in brain metabolism of the drugs studied and again, that a differential behavior between Enflurane and Isoflurane existed, supporting our previous findings. High levels of CYP2E1 have been associated with cellular oxidative stress and it could be related with the onset of acute attacks by drugs in porphyrias.