Abstract

Norcocaine nitroxide was found to be produced via the one-electron oxidation of N-hydroxynorcocaine by hepatic microsomal enzymes from induced and noninduced rats, hamsters, and mice in the presence of an NADPH-generating system. This reaction was demonstrated to be mediated by cytochrome P-450 as suggested by induction experiments using phenobarbital, which markedly enhanced the production of this nitroxide, and by the inhibition of this monooxygenase by metyrapone, which depressed the formation of this free radical. Unlike other nitroxides, norcocaine nitroxide was rapidly reduced by flavoproteins such as cytochrome P-450 reductase and FAD-monooxygenase, but not cytochrome P-450. We believe that since NADPH is consumed during the futile cycling of N-hydroxynorcocaine/norcocaine nitroxide and since NADPH is an essential cofactor of the glutathione reductase system, diminished reduced nucleotide may lead to depressed levels of cellular glutathione. In this manner, we theorize that cocaine initiates hepatotoxicity.