Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Lloyd, R.V. et al.

Reexamination of the microsomal transformation of N-hydroxynorcocaine to norcocaine nitroxide.

Cocaine is known to be associated with hepatotoxicity in laboratory animals, and there is recent evidence that it also induces liver damage in humans. In both cases an N-oxidative pathway is responsible. Cocaine (NCN) is first N-demethylated to norcocaine, followed by oxidation to N-hydroxynorcocaine (NCNOH) and norcocaine nitroxide (NCNO.). On the basis of ESR studies of NCNOH with rat liver microsomes, it has been proposed that NCNO. induces hepatotoxicity by futile redox cycling between NCNO. and NCNOH at the expense of NADPH. The reaction is reported to be accompanied by formation of superoxide and lipid peroxyl radicals. It has also been reported that the same toxic sequence occurs with rat brain microsomes, leading to the formation of reactive free radicals in the brain. We have reexamined the microsomal metabolism of NCNOH to investigate the mechanism more thoroughly. Spin traps [5,5-dimethyl-1-pyrroline N-oxide and alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone] were used to investigate the formation of reactive free radicals, including superoxide, in liver and brain microsomal incubations. In agreement with the literature, we detected a six-line spectrum of a radical adduct of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone from liver microsome incubations. In contrast, our results showed that brain microsomes were completely inactive, contrary to the literature. In addition, we did not find any NCNO.- or NCNOH-dependent formation of superoxide with either brain or liver microsomes.[1]

References

Reexamination of the microsomal transformation of N-hydroxynorcocaine to norcocaine nitroxide. Lloyd, R.V., Shuster, L., Mason, R.P. Mol. Pharmacol. (1993) [Pubmed]

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