N-ARALKYL DERIVATIVES OF 1-AMINOBENZOTRIAZOLE AS POTENT ISOZYME-SELECTIVE MECHANISM-BASED INHIBITORS OF RABBIT PULMONARY CYTOCHROME-P450 INVIVO

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 pulmona ry P450 in vitro (Mathews and Bend, 1986; Woodcroft et al., 1990). The se three compounds were compared as inhibitors in vivo after i.v. admi nistration to rabbits treated with the cytochrome P450 inducers beta-n aphthoflavone or phenobarbital. By 1 hr after administration of N-alph a-methylbenzyl-1-aminobenzotriazole (1 mumol/kg), 80% of P450 2Bs-cata lyzed benzphetamine N-demethylation in lung of beta-naphthoflavone-tre ated rabbits was inactivated and about 35% of P450 was lost without in hibition of P450 1 Al -catalyzed activity; at a dose of 10 or 100 mumo l/kg, this compound totally inactivated pulmonary P450 2Bs activity wh ile 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 mu mol/kg) of these compounds were compared in phenobarbital-induced rabb its. Virtually all (-95%) of pulmonary P450 2Bs-dependent activity was inhibited by the two N-aralkylated compounds (vs. 50% for 1-aminobenz otriazole). At this dose, about 25% of hepatic P450 was destroyed by a ll 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, respective ly. Our data demonstrate that N-a-methylbenzyl-1-aminobenzotriazole an d N-benzyl-1-aminobenzotriazole, but not 1-aminobenzotriazole, are hig hly selective for the inactivation of pulmonary P450 2Bs in rabbits in vivo.