REEXAMINATION OF THE MICROSOMAL TRANSFORMATION OF N-HYDROXYNORCOCAINETO NORCOCAINE NITROXIDE

Cocaine is known to be associated with hepatotoxicity in laboratory an imals, and there is recent evidence that it also induces liver damage in humans. In both cases an N-oxidative pathway is responsible. Cocain e (NCN) is first N-demethylated to norcocaine, followed by oxidation t o N-hydroxynorcocaine (NCNOH) and norcocaine nitroxide (NCNO.). On the basis of ESR studies of NCNOH with rat liver microsomes, it has been proposed that NCNO. induces hepatotoxicity by futile redox cycling bet ween NCNO. and NCNOH at the expense of NADPH. The reaction is reported to be accompanied by formation of superoxide and lipid peroxyl radica ls. It has also been reported that the same toxic sequence occurs with rat brain microsomes, leading to the formation of reactive free radic als in the brain. We have reexamined the microsomal metabolism of NCNO H to investigate the mechanism more thoroughly. Spin traps [5,5-dimeth yl-1-pyrroline N-oxide and alpha-(4-pyridyl-1-oxide)-N-tert-butylnitro ne] were used to investigate the formation of reactive free radicals, including superoxide, in liver and brain microsomal incubations. In ag reement with the literature, we detected a six-line spectrum of a radi cal adduct of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone from liver microsome incubations. In contrast, our results showed that brain mic rosomes were completely inactive, contrary to the literature. In addit ion, we did not find any NCNO.- or NCNOH-dependent formation of supero xide with either brain or liver microsomes.