The role of cytochrome P-4502E1 in the neurochemical effects produced by MDMA
Description
The drug 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as 'Ecstasy', is a synthetic amphetamine analogue that possesses neurotoxic properties in the rat. The neurotoxicity produced by MDMA is characterized by a chronic depletion of serotonin and 5-HIAA, inhibition of tryptophan hydroxylase and the destruction of serotonergic nerve axon terminals in the brain. The mechanism by which MDMA produces this neurotoxicity is unknown. However, a popular theory is that this neurotoxicity is mediated by a metabolite of MDMA and not by the parent compound. Thus, the purpose of this present study was to investigate further the role of metabolism in the mediation of the neurotoxicity produced by MDMA. Since MDMA is metabolized by a family of enzymes known as cytochrome P450, a specific isozyme may be responsible for the formation of a neurotoxic metabolite, or metabolites, from MDMA The present study suggests that cytochrome P4502E1 (CYP2E1), a specific isozyme of cytochrome P450, may be involved in the formation of a neurotoxic metabolite from MDMA. This study found that the completion of serotonin produced by MDMA can be attenuated or blocked by the inhibition of CYP2E1 activity. Three distinct inhibitors of CYP2E1 were used in this study including, disulfiram, acetone and the physiologic condition of fasting. All three attenuated the depletion of serotonin in cerebral cortex produced by the subcutaneous administration of MDMA Additionally, the intracerebroventricular administration of an ultrafiltrate extract of a microsomal preparation incubated in the presence of MDMA caused the depletion of serotonin in cerebral cortex at seven days. The degree of depletion of serotonin was linear with respect to the incubation time of the microsomal preparation containing MDMA. Furthermore, the ability of the ultrafiltrate extract to deplete serotonin was blocked by the incubation of the microsomal preparation with MDMA in the presence of acetone, the CYP2E1 inhibitor. Taken together, these observations suggest that CYP2E1 is involved in the formation of a neurotoxic metabolite from MDMA