Determination of the human cytochrome P450s involved in the metabolism of 2n -propylquinoline

Abstract

1 2 n -Propylquinoline (2 n PQ) is a newly developed drug for visceral antileishmaniasis and its activity has been previously evaluated in mice following oral administration. The study was carried out to investigate the kinetic formation of 2 n PQ metabolites and to characterize the human liver CYP forms involved in its oxidative metabolism. 2. The inhibition of 2 n PQ metabolite formation by specific substrates or inhibitors of CYP forms and correlation studies were performed in human liver microsomes. 2 n PQ biotransformation was then studied in human lymphoblasts expressing specific CYPs and microsomal epoxide hydrolase. 3. Three major metabolites were produced by human liver microsomes and their structures were identified by ESI-LC/MS: dihydroxy-2 n -propylquinoline, 3'-hydroxy-2 n -propylquinoline and 1'-hydroxy-2 n -propylquinoline. An intermediary metabolite, epoxy-2 n -propylquinoline, formed by CYP was also biotransformed by microsomal epoxide hydrolase into dihydroxy-2 n -propylquinoline. 4. 2 n PQ oxidation follows Michaelis-Menten kinetics. In human liver microsomes, its metabolism was extremely inhibited by pilocarpine, coumarin and diethyldithiocarbamate. From a panel of 12 human liver microsome samples, the rate of 2 n PQ oxidation was highly correlated with the activities of CYP2A6 and CYP2E1. Human lymphoblasts expressing specific CYPs showed the involvement of CYP2A6, CYP2E1 and CYP2C19. 5. The results indicate that 2 n PQ metabolites are 3'- and 1'-hydroxylated by human liver microsomes and an epoxy-2 n -propylquinoline is biotransformed into a dihydroxy-2 n -propylquinoline by microsomal epoxide hydrolase.