Metabolism of MPTP by cytochrome P4502D6 and the demonstration of 2D6 m RNA in human foetal and adult brain by in situ hybridization

Abstract

1. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product ofsynthetic 'street ' heroin, is known to cause Parkinson's Disease-like symptoms in man. 2. The mechanism of action of this neurotoxin is thought to involve activation by the monoamine oxidase B system and subsequent toxicity by inhibition of neuronal mitochondrial respiration. The manifestation of toxicity will be abalance between the rate of activation of this compound versus its rate of inactivation through metabolism by enzymes such as the cytochrome P450-dependent monooxygenases. 3. In this report we demonstrate that MPTP N -demethylation, a detoxification pathway, is catalysed by cytochrome P450 CYP2D6 and up to 40% of the hepatic metabolism is mediated by this enzyme. 4. Perhaps more importantly we alsodemonstrate by in situ hybridization thatCYP2D6 is localized in the pigmented neurons of the substantia nigra indicating that 2D6-mediated detoxification will occur in target cells. 5. These datapresent evidence thatCYP2D6 will be afactorin susceptibility to MPTP neuronal toxicity and provide a biochemical rationale for the genetic observations linking a polymorphism at the CYP2D6 locus with susceptibility to Parkinson's.