PT  - JOURNAL ARTICLE
AU  - Knickle, L C
AU  - Webb, C D
AU  - House, A A
AU  - Bend, J R
TI  - Mechanism-based inactivation of cytochrome P450 1A1 by N-aralkyl-1-aminobenzotriazoles in guinea pig kidney in vivo and in vitro: minimal effects on metabolism of arachidonic acid by renal P450-dependent monooxygenases.
DP  - 1993 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 758--764
VI  - 267
IP  - 2
4099  - http://jpet.aspetjournals.org/content/267/2/758.short
4100  - http://jpet.aspetjournals.org/content/267/2/758.full
SO  - J Pharmacol Exp Ther1993 Nov 01; 267
AB  - Guinea pig renal microsomes convert arachidonic acid to two classes of P450-dependent metabolites, epoxyeicosatrienoic acids (EET), and 16- through 20-hydroxyeicosatetraenoic acids [(16-20)-OH-AA)]. The rate of formation of these metabolites was not altered by beta-naphthoflavone induction, which increased P450 1A1-dependent 7-ethoxyresorufin O-deethylation activity approximately 100-fold. alpha-Naphthoflavone, which inhibits renal P450 1A1 in vitro, did not inhibit the formation of these metabolites in microsomes from induced animals. In induced animals, N-benzyl-1-aminobenzotriazole and N-alpha-methylbenzyl-1-aminobenzotriazole, administered i.v., inhibited microsomal 7-ethoxyresorufin O-deethylation activity by approximately 50% without inhibiting the formation of either class of arachidonic acid metabolites. In vitro these mechanism-based inhibitors inactivated 1A1 by > 90% without inhibiting EET or (16-20)-OH-AA formation. These data show that P450 1A1 does not bioactivate arachidonic acid to either (16-20)-OH-AA or EET in guinea pig kidney, and that N-benzyl-1-aminobenzotriazole and N-alpha-methylbenzyl-1-aminobenzotriazole selectively inactivate P450 1A1 in comparison to the P450 isozyme(s) that metabolize arachidonic acid in the kidney. In guinea pig liver beta-naphthoflavone treatment, which induces P450 1A1 and 1A2, increased the rate of the formation of (16-20)-OH-AA and EET and in vitro alpha-naphthoflavone inhibited the formation of these metabolites in induced hepatic microsomes by approximately 50 and approximately 35%, respectively. These data demonstrate that a beta-naphthoflavone-inducible isozyme, most likely 1A2, converts arachidonic acid to both (16-20)-OH-AA and EET in guinea pig liver.