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Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and its effects are modulated by dopaminergic neurotransmission. Dopamine availability in prefrontal cortex is mostly controlled by catechol-o-methyltransferase (COMT) and it has been suggested that THC induced psychosis and cognitive impairment are dependent on COMT genotype. However the effect of THC in COMT activity is not known.This study aims to evaluate the effect of THC on COMT activity and monoamines tissue levels in mice prefrontal cortex. COMT activity in vitro and in vitro ex-vivo was evaluate in the pre-frontal cortex from C57BL/6J mice. For 10 days, mice were treated either with vehicle or THC (10 mg/Kg bw, total daily dose).In vitro, THC produced a concentration dependent inhibition in brain COMT activity with an IC 50 value of 232 µM. In vivo, THC treatment did not change monoamines or dopamine metabolites in prefrontal cortex. Nevertheless a significant decrease in 5-hydroxyindoleacetic acid (0.35±0.1, 0.54±0.02 pmol/mg tissue for control and THC respectively) was observed. In vitro-ex-vivo, COMT activity in the pre-frontal cortex showed no differences in the enzyme kinetics parameters when comparing THC to control animals. Analysis from the saturation curves found that the Vmax values (in nmol/mg prot/h) were 2.73 (2.4, 3.1) and 2.70 (2.3, 3.1) for CT and THC respectively.In conclusion, THC decreases COMT activity in vitro only in high concentrations (above 100 µM), however when administrated in vivo no significant effect was observed in enzyme activity or dopamine prefrontal cortex metabolism.

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A intoxicação pelo paracetamol, ou acetaminofeno, constitui uma das principais causas de insuficiência hepática aguda, no entanto, o mecanismo preciso de hepatotoxicidade deste fármaco ainda possui muitas questões em aberto.Na intoxicação pelo paracetamol, é formado um metabolito extremamente reativo, a N-acetil-p-benzoquinonaimina (NAPQI), que se acumula em quantidades de tal ordem, que superam a capacidade das vias inativadoras, nos hepatócitos. A NAPQI é particularmente tóxica para as mitocôndrias, desacoplando a cadeia respiratória, levando ao stress oxidativo e à disfunção mitocondrial. A disfunção destes organelos, combinada com a fragmentação nuclear associada, culminam na necrose dos hepatócitos. Ao mesmo tempo, o stress oxidativo ativa as vias de sinalização c-jun-N-terminal kinase (JNK), p53, fissão mitocondrial, stress do retículo endoplasmático e aumento do cálcio citoplasmático, que exacerbam a toxicidade hepática do paracetamol, enquanto que vias de sinalização, como a nuclear factor-like 2 (Nrf2) e a mitofagia, mostraram um papel de contrarregulação deste mecanismo.A seguir à necrose dos hepatócitos, o sistema imune é chamado a intervir e cada um dos tipos de células efetoras poderá ter um papel potenciador ou protetor da lesão hepática. / Acetaminophen or paracetamol overdose is a main cause of acute liver failure, however the precise hepatotoxicity's mechanism of this medicine still has questions to be answered.In acetaminophen overdose, is formed one extremely reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which accumulates so much that overcome the capacity of the inactivation pathways, in the hepatocytes. NAPQI is particularly toxic to mitochondria, uncoupling the respiratory chain, leading to oxidative stress and mitochondrial dysfunction. The dysfunction of this organelles, combined with the associated nuclear fragmentation, culminates in hepatocyte necrosis. Meanwhile, oxidative stress activates metabolic pathways such as c-jun-N-terminal kinase (JNK), p53, mitochondrial fission, endoplasmic reticulum stress and increasing cytoplasmic calcium, which promotes acetaminophen hepatic toxicity, on the other hand, metabolic pathways such as nuclear factor-like 2 (Nrf2) and mitophagy, that have demonstrated a contrarregulatory role of this mechanism.Next to hepatocyte necrosis, the immune system is called to intervene and each one of the cells types could have a damaging or a protecting role on the liver failure.