In vitro hepatic and extra-hepatic reduction of (−)-nicotine-1′-N-oxide in rats

The anaerobic reduction of (−)-nicotine-1′-N-oxide was studied in various tissues of the rat. Gas—liquid chromatography was employed in the quantitative determination of unchanged drug and its metabolites. With the exception of blood and brain most tissues reduced (−)-nicotine-1′-N-oxide in the following order: liver > small intestine > kidney > heart > lung. The predominant cellular sites for reduction of the N-oxide were the microsomes and soluble fraction. The reductases were non-specific with regard to their requirement for NADH and NADPH although the latter was more effective. Air or boiling abolished all the reducing activity of the reductases in all fractions studied. SKF525-A and EDTA caused partial inhibition whereas CO or KCN effected almost complete inhibition. Flavins and Phenobarbital enhanced the activity of the (−)-nicotine-1′-N-oxide reductase(s). It was concluded that (−)-nicotine-1′-N-oxide reductase(s) could be flavoproteins linked to P-450 and/or to NADPH and appear to be different from other known reductases.