N-aralkylated derivatives of 1-aminobenzotriazole are potent isozyme- and lung-selective mechanism-based inhibitors of guinea pig cytochrome P-450 in vivo.
1-Aminobenzotriazole (ABT) and its N-benzyl-1-aminobenzotriazole (BBT) and N-alpha-methylbenzyl (alpha-MB) derivatives were compared as isozyme-selective, lung-selective (vs. liver) mechanism-based inhibitors of cytochrome P-450 (P450) in noninduced, beta-naphthoflavone-induced and phenobarbital-induced guinea pigs 4 hr after i.v. administration. Isozyme-selective monooxygenase activities for lung P450 1A1, 2B4 and 4B1 orthologues (7-ethoxyresorufin O-deethylation for guinea pig P450 1A1, 7-pentoxyresorufin O-depentylation for P450 2Bx and 4-aminobiphenyl N-hydroxylation for P450 4Bx, respectively) were determined in pulmonary and hepatic microsomes. BBT and alpha-MB inactivated pulmonary P450 in an isozyme-selective manner; in non- and phenobarbital-induced animals the order of inactivation was 2Bx > 1A1 >>> 4Bx. In beta-naphthoflavone-induced animals, alpha-MB specifically inhibited 2Bx in the lung (>90% inactivation at 0.075 mumol/kg, whereas a 100-fold higher dose did not inhibit 4Bx or 1A1). BBT and alpha-MB also were highly selective for the inactivation of pulmonary vs. hepatic P450. In each case at least one of the doses administered caused marked inactivation of pulmonary 2Bx (>80% with alpha-MB and 50-70% with BBT) without inhibiting the hepatic monooxygenase activities. In contrast, ABT displayed little isozyme-selectively and little tissue-selectivity. The differences in tissue-selectivity of the inhibitors are due to BBT and alpha-MB being much more potent (100- to 1000-fold) inactivators of pulmonary P450 2Bx than ABT consistent with BBT and alpha-MB, but not ABT, serving as substrates for the lipophilic aromatic amine uptake system in the lung. In summary, BBT and alpha-MB, at appropriate doses, are isozyme-selective/specific (P450 2Bx), lung-specific inhibitors of P450 in guinea pig in vivo.
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
L C
LC
Knickle
R M
RM
Philpot
J R
JR
Bend
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004789:Enzyme Activation; D006168:Guinea Pigs; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D012680:Sensitivity and Specificity; D014230:Triazoles / Q000494:pharmacology*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D014230:Triazoles; C067013:N-benzyl-1-aminobenzotriazole; C059849:alpha-methylbenzylaminobenzotriazole; C033020:1-aminobenzotriazole; D019324:beta-Naphthoflavone; D010634:Phenobarbital