N-aralkyl derivatives of 1-aminobenzotriazole as potent isozyme-selective mechanism-based inhibitors of rabbit pulmonary cytochrome P450 in vivo

Abstract

Two N-aralkylated (N-benzyl-and N-alpha-methylbenzyl-) derivatives of 1-aminobenzotriazole, a mechanism-based inhibitor of cytochrome P450 with low isozyme selectivity, were previously shown to be potent and isozyme-selective suicide substrates for rabbit and guinea pig pulmonary P450 in vitro (Mathews and Bend, 1986; Woodcroft et al., 1990). These three compounds were compared as inhibitors in vivo after i.v. administration to rabbits treated with the cytochrome P450 inducers beta-naphthoflavone or phenobarbital. By 1 hr after administration of N-alpha-methylbenzyl-1-aminobenzotriazole (1 mumol/kg), 80% of P450 2Bs-catalyzed benzphetamine N-demethylation in lung of beta-naphthoflavone-treated rabbits was inactivated and about 35% of P450 was lost without inhibition of P450 1A1-catalyzed activity; at a dose of 10 or 100 mumol/kg, this compound totally inactivated pulmonary P450 2Bs activity while exerting minimal effects on benzphetamine N-demethylation activity (< 20% inhibition) in liver of beta-naphthoflavone-treated rabbits. N-benzyl-1-aminobenzotriazole was also an isozyme- and tissue-selective inhibitor of pulmonary P450 2Bs in vivo. Relatively high doses (100 mumol/kg) of these compounds were compared in phenobarbital-induced rabbits. Virtually all (> or = 95%) of pulmonary P450 2Bs-dependent activity was inhibited by the two N-aralkylated compounds (vs. 50% for 1-aminobenzotriazole). At this dose, about 25% of hepatic P450 was destroyed by all three compounds, whereas 1-aminobenzotriazole and its N-benzyl and N-alpha-methylbenzyl derivatives inactivated 20, 50 and 85% of hepatic P450 2Bs-selective benzphetamine N-demethylation activity, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)