Metabolism of cocaine and norcocaine to N-hydroxynorcocaine

doi:10.1016/0006-2952(83)90247-2

Biochemical Pharmacology

Volume 32, Issue 20, 15 October 1983, Pages 3045-3051

https://doi.org/10.1016/0006-2952(83)90247-2 Get rights and content

Abstract

The mixed function oxidase system of mouse liver microsomes converts norcocaine to N-hydroxynorcocaine (NHNC). This metabolite can be measured by high performance liquid chromatography (HPLC) using an electrochemical detector. Experiments with inducers and inhibitors suggested that the cytochrome P-450 system was responsible for most of the formation of NHNC. NHNC was relatively unstable under physiological conditions, with a T_$12$ of 17 min at pH 7.4 and 37°. HPLC with the electrochemical detector was also used to demonstrate the formation of NHNC in vivo when mice were injected with norcocaine or cocaine.

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Increased toxicity of cocaine to human hepatocytes is observed when cells are simultaneously incubated with ethanol. Ethanol might exacerbate cocaine hepatocyte toxicity by three different pathways: a) by increasing the oxidative metabolism of cocaine and hence the oxidative damage; b) by the formation of a more toxic metabolite, namely cocaethylene; or c) by decreasing the defence mechanisms of the cell (i.e. GSH). In the present study, experiments were conducted to investigate the feasibility of these hypotheses. In hepatocytes preincubated for 48 hr with ethanol, neither significant changes in cocaine metabolism nor cytotoxicity were found despite differences in hepatocyte p-nitrophenol hydroxylase (largely CYP2E1 activity). Cocaethylene, the transesterification product of cocaine and ethanol, was found to be more toxic than cocaine for human hepatocytes (3x). However, the small amount formed when human hepatocytes were incubated with cocaine and ethanol would hardly explain the increased toxicity observed. On the other hand, the simultaneous presence of cocaine and ethanol caused a sustained decline in the intracellular GSH content that was larger than that observed in cocaine- or ethanol-treated cultures. Parallel to this phenomenon, a significant increase in lipid peroxidation was observed, as compared to cells treated with equimolar amounts of cocaine, ethanol, or cocaethylene. Finally, depletion of hepatocyte GSH with diethylmaleate down to levels similar to those found in ethanol-treated cells made hepatocytes more susceptible to cocaine. Taken together, the results of this research suggest that by decreasing GSH levels, ethanol makes human hepatocytes more sensitive to cocaine-induced oxidative damage.
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Metabolism of cocaine and norcocaine to N-hydroxynorcocaine

Abstract

Biochem. Pharmac.

Biochem. Pharmac.

Biochem. Pharmac.

Biochem. Pharmac.

J. med. Chem.

J. biol. Chem.

Toxic. appl. Pharmac.