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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.

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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Knickle LC,Bend JR

subject

Has Abstract

pub_date

1994-06-01 00:00:00

pages

1273-80

issue

6

eissn

0026-895X

issn

1521-0111

journal_volume

45

pub_type

杂志文章

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