Species differences in pulmonary N-oxidation of chlorpromazine and imipramine

Our previous studies have demonstrated that chlorpromazine (CPZ) and imipramine (IMP) are metabolized appreciably via N-oxidation catalyzed by pulmonary microsomal flavin monooxygenase in the rat but not in the rabbit. The present work deals with the species differences in N-oxidase of pulmonary microsomes from male cat, dog, goat, guinea pig, hamster, mouse, pig, rabbit and rat. Although CPZ-N-oxidizing activities were generally higher than IMP-N-oxidizing activities, the CPZ-/IMP-oxidizing activity ratios were not constant among the species tested. Little or no activity was detected in the guinea pig and rabbit lung. The following ranking was assigned: mouse less than hamster less than pig less than rat less than dog less than cat less than guinea pig less than goat less than rabbit for CPZ, and pig less than rat less than mouse less than dog less than hamster less than cat less than guinea pig less than goat less than rabbit for IMP. Nitrosobenzene, a known inhibitor of N-oxidase reductase, inhibited rather than increasing the N-oxidation of both substrates. Therefore, it is unlikely that the marked species differences in pulmonary N-oxidase activities are due to differences in N-oxide reductase. Optimum pH for CPZ-N-oxidase was relatively broad over a range of 7.4-8.5 for rat and 8-9.5 for other species. The pH optima for IMP-N-oxidase ranged from 8.5 to 9.5. n-Octylamine accelerated CPZ-N-oxidation in most species. IMP-N-oxidation was affected to a lesser extent by this primary amine. DPEA (2,4-dichloro-6-phenyl- phenoxyethylamine ) also stimulated the CPZ-N-oxidation in rat, pig and cat but inhibited IMP-N-oxidation in these species.(ABSTRACT TRUNCATED AT 250 WORDS)