Metabolism of cocaine and norcocaine to N-hydroxynorcocaine

Shuster, Louis; Casey, Erin M.; Welankiwar, Sudhakar S.

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

Cited by 39 publications

(13 citation statements)

References 8 publications

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“…While dose, strain, and type of administration all affect pharmacokinetics, our estimates of cocaine and methamphetamine concentrations in the brain and blood are within the range observed in other studies for methamphetamine (Brien et al 1978;Fornai et al 1999;Hendrickson et al 2004;Won et al 2001) and cocaine (Azar et al 1998;Benuck et al 1987;Miller et al 1996;Pan and Hedaya 1998;Reith et al 1987). Additionally, the primary routes of metabolism in mice (Boyer and Petersen 1992;Shuster et al 1983) are similar to those in rats (Estevez et al 1977) and humans (Bencharit et al 2003;Brzezinski et al 1997).…”

Section: Limitationsmentioning

confidence: 72%

Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice

2008

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Section: Limitationsmentioning

confidence: 72%

Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice

2008

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“…Cocaine is N-demethylated to norcocaine and further converted to N-hydroxynorcocaine. The presence of norcocaine has been demonstrated in man (Inaba et al 1978;Jindal et al 1978;Lowry et al 1979), whereas N-hydroxynorcocaine has been identified in rats and mice only (Evans 1983;Shuster et al 1983;Jindal and Lutz 1986;Benuck et al 1988). When administered to mice at equimolar doses, norcocaine was demonstrated to be more hepatotoxic than the cocaine parent molecule, and N-hydroxynorcocaine was the most potent species of all (Thompson et al 1979).…”

Section: Metabolic Pathwaysmentioning

confidence: 92%

“…1). P-450-dependent monooxygenases are involved in all three metabolic steps up to norcocaine nitroxide formation (Shuster et al 1983). An emerging area of research is the implication of individual forms of P-450 in cocaine bioactivation and cytotoxicity.…”

Section: Role Of Cytochrome P-450 and Fad-containing Monooxygenasesmentioning

confidence: 99%

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Boelsterli

Göldlin

1991

Arch Toxicol

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Cocaine is an intrinsic hepatotoxin in laboratory animals, and there is growing evidence that high doses of cocaine can precipitate hepatic necrosis in humans. The rodent model of cocaine hepatotoxicity is commensurate with the concept that a multistep mainly cytochrome P-450 dependent N-oxidative pathway is responsible for the expression of hepatocellular injury. Among the possible biomechanisms by which cocaine exerts its cytotoxic effects, direct oxidative damage by reactive oxygen species generated by redox cycling during the metabolic cascade seems most important. The role of the ensuing lipid peroxidation and protein thiol oxidation is less clear. Similarly, the functional role of irreversible (covalent) binding of a not yet defined electrophilic cocaine intermediate to hepatocellular proteins remains enigmatic so long as the critical molecular targets have not been identified. Finally, glutathione plays a pivotal protective role against cocaine-induced hepatic injury. Interactions with ethanol or inducers of the expression of the cytochrome P-450IIB subfamily can potentiate cocaine hepatotoxicity. Thus, the net amount of the ultimate reactive species seems to determine the severity of the hepatic lesions and to be responsible for the marked interspecies, interstrain, and sex differences. Recent advances in culture techniques of hepatocytes and precision-cut liver slices from various species including man have made it possible to correlate cocaine biotransformation with cytotoxicity and to selectively study the putative cellular mechanisms. Clearly, more studies are necessary to further illuminate our understanding of the role of the biochemical and molecular events precipitating hepatic necrosis during cocaine-mediated hepatotoxicity.

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“…and N-hydroxynorcocainc [17] were sepa rated using a Waters Associates chromatography em ploying the 15-cm steel Nova-Pak C 18 column or RCM C18 cartridge, as previously described [18]. For electro chemical detection of N-hvdroxynorcocaine.…”

Section: High-pressure Liquid Chromatographymentioning

confidence: 99%

Norcocaine and N-Hydroxynorcocaine Formation in Human Liver Microsomes: Role of Cytochrome P-450 3A4

et al. 1993

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Cocaine was metabolized to norcocaine by microsomes prepared from lymphoblastoid cells expressing transfected human P-450 3A4. The specific activities of norcocaine formation by microsomes prepared from three human liver samples correlated with the amount of P-450 3A immunoreactive protein detected by immunoblot. Triacetyloleandomycin, a specific inhibitor of P-450 3A isoforms, inhibited formation of norcocaine from cocaine, but not formation of N-hydroxynorcocaine from norcocaine. The chemical identity of the norcocaine and N-hydroxynorcocaine produced by human liver microsomes was established by combination of gas chromatography and mass spectrometry. Thus, human P-450 3A4 is a cocaine demethylase, and P-450 isoforms of the 3 A family are responsible for the majority of norcocaine production by human hepatic microsomes.

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Metabolism of cocaine and norcocaine to N-hydroxynorcocaine

Cited by 39 publications

References 8 publications

Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice

Evaluation of a pharmacokinetic hypothesis for reduced locomotor stimulation from methamphetamine and cocaine in adolescent versus adult male C57BL/6J mice

Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites

Norcocaine and N-Hydroxynorcocaine Formation in Human Liver Microsomes: Role of Cytochrome P-450 3A4

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