N-DEMETHYLATION OF COCAINE TO NORCOCAINE - EVIDENCE FOR PARTICIPATION BY CYTOCHROME-P-450 AND FAD-CONTAINING MONOOXYGENASE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 23  (2) , 482-485
Abstract
Experiments were conducted to determine which microsomal enzymes are involved in the in vitro hepatic oxidative N-demethylation of cocaine [a CNS stimulant which is hepatotoxic in mice] to norcocaine, the first step in the biotransformation of cocaine to its ultimate hepatotoxic metabolite. Cocaine was converted to norcocaine by 2 alternate pathways, one involving only cytochrome P-450 and the other requiring both cytochrome P-450 and FAD-containing monooxygenase. In the first pathway, cocaine was directly N-demethylated to norcocaine by cytochrome P-450; this reaction was enhanced by phenobarbital induction and was inhibited by both N-octylamine and metyrapone. The 2nd route was a 2-step reaction involving cocaine N-oxide as an intermediate. In this pathway, cocaine is first oxidized to cocaine N-oxide by FAD-containing monooxygenase, followed by a cytochrome P-450-catalyzed N-demethylation to norcocaine. This latter step was enhanced by phenobarbital treatment and inhibited by N-octylamine. Cocaine N-oxide also exhibited a Type I binding spectrum with mouse hepatic microsomes. A model system consisting of ferrous sulfate catalyzed the N-demethylation of cocaine N-oxide. Cytochrome P-450 and FAD-containing monooxygenase evidently participate in the initial oxidation of cocaine to norcocaine. A mechanism to account for the conversion of cocaine N-oxide to norcocaine is proposed.