Sélection de la langue

Gouvernement du Canada / Government of Canada

Recherche

N-aralkylated derivatives of 1-aminobenzotriazole are potent isozyme- and lung-selective mechanism-based inhibitors of guinea pig cytochrome P-450 in vivo

Par Conseil national de recherches du Canada

Lienhttp://jpet.aspetjournals.org/content/270/1/377
AuteurRechercher : ; Rechercher :
FormatTexte, Article
Résumé
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.
Date de publication
Maison d’éditionAmerican Society for Pharmacology and Experimental Therapeutics
Dans
  • Journal of Pharmacology and Experimental Therapeutics 270, nº 1 : 377–385.
Langueanglais
Publications évaluées par des pairsOui
Publication du CNRC
Cette publication n’est pas du CNRC

Ce sont des publications qui ont été rédigées par un auteur du CNRC, mais avant que celui-ci soit employé du CNRC.

Numéro NPARC23000936
Exporter la noticeExporter en format RIS
Signaler une correctionSignaler une correction (s'ouvre dans un nouvel onglet)
Identificateur de l’enregistrement4884e3cc-eb17-4cb6-965c-044e1cdd58e7
Enregistrement créé2016-11-18
Enregistrement modifié2022-10-17
Date de modification :