NORCOCAINE NITROXIDE - A POTENTIAL HEPATOTOXIC METABOLITE OF COCAINE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 21  (2) , 458-463
Abstract
Norcocaine nitroxide was produced via the 1-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 mediated by cytochrome P-450, demonstrated 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. 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. Evidently, in this manner, cocaine initiates hepatotoxicity.