Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism

doi:10.1016/0003-9861(88)90340-2

Archives of Biochemistry and Biophysics

Volume 261, Issue 2, March 1988, Pages 257-263

https://doi.org/10.1016/0003-9861(88)90340-2 Get rights and content

Abstract

A new generation of heteroatom analogs of arachidonic acid are documented as powerful and selective inhibitors of the cytochrome P-450-dependent arachidonic acid oxygenase reaction (IC₅₀, 5–10 μm) with little effect on either cyclooxygenase or soybean lipoxidase at 100 μm. The imidazole derivatives, ketoconazole and clotrimazole, are potent and selective inhibitors of the arachidonic acid epoxygenase and lipoxidase-like activities of phenobarbital-induced rat liver microsomal fractions (IC₅₀, 2.0 and 0.3 μm, respectively). In contrast, the $ω ωw-1$ oxygenase activity of ciprofibrate-induced microsomal fractions was relatively resistant to inhibition by these compounds (IC₅₀, 50 and 25 μm for ketoconazole and clotrimazole, respectively). Nordihydroguaiaretic acid (NDGA), eicosatetraynoic acid (ETYA), and indomethacin, extensively utilized inhibitors of the cyclooxygenase and lipoxygenase branches of the arachidonate cascade, also inhibit cytochrome P-450-dependent arachidonic acid metabolism. In decreasing order of potency, they were NDGA, ETYA, and indomethacin (IC₅₀,15, 40, and 70 μm, respectively).

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^☆: This work was supported by Grants USPHS GM 31278, GM 37922, and CA 30253, and the Robert A. Welch Foundation (1-782).

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Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism☆

Abstract

Trends Pharmacol. Sci

Arch. Biochem. Biophys

Prostaglandins

Biochem. Pharmacol

Tetrahedron Lett

J. Biol. Chem

Arch. Biochem. Biophys

Arch. Biochem. Biophys

Prostaglandins