Bioactivation of arachidonic acid by the cytochrome P450 monooxygenases of guinea pig lung: the orthologue of cytochrome P450 2B4 is solely responsible for formation of epoxyeicosatrienoic acids

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Linkhttp://molpharm.aspetjournals.org/content/45/6/1273
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FormatText, Article
Journal titleMolecular Pharmacology
ISSN0026-895X
1521-0111
Volume45
Issue6
Pages1273–1280
Abstract
Guinea pig lung microsomes converted arachidonic acid (AA) to two classes of cytochrome P450 (P450)-dependent metabolites, 16- through 20-hydroxyeicosatetraenoic acids [(16-20)-OH-AA] and epoxyeicosatrienoic acids (EETs). The rate of formation of (16-20)-OH-AA was approximately 3-fold higher in microsomes from beta-naphthoflavone-induced versus untreated animals. In microsomes from untreated or induced animals EETs, the major class of P450 metabolites in guinea pig lung, were formed in a regioselective manner, with 8,9-, 11,12-, and 14,15-regioisomers accounting for > or = 90% of the total EETs. With isozyme-selective inhibitors and inhibitory antibodies the role of individual pulmonary P450 isozymes in AA metabolism was examined. Metyrapone and SKF-525A (P450 2B selective) inhibited EET formation by > or = 85% with little effect on (16-20)-OH-AA formation. 1-Aminobenzotriazole (1 mM), a mechanism-based inhibitor with low isozyme selectivity, inhibited the formation of both classes of metabolites by > 95%, whereas N-alpha-methylbenzyl-1-aminobenzotriazole (1 microM), a P450 2B-selective mechanism-based inhibitor, abolished EET formation with little effect on (16-20)-OH-AA formation. Antibodies to rabbit P450 2B4 also abolished EET formation without inhibiting the formation of (16-20)-OH-AA, whereas antibodies to rabbit P450 4B1 did not inhibit the formation of either class of metabolites. alpha-Naphthoflavone (P450 1A1 selective in lung) did not inhibit the formation of either class of metabolites. These data demonstrate that the guinea pig orthologue of P450 2B4 is solely responsible for the bioactivation of AA to EETs in guinea pig lung and that a form of P450 other than a 2B, 4B, or 1A isozyme, which is inducible by beta-naphthoflavone, is responsible for (16-20)-OH-AA formation.
Publication date
PublisherAmerican Society for Pharmacology and Experimental Therapeutics
LanguageEnglish
Peer reviewedYes
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NPARC number23000935
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