TY - JOUR
T1 - Inhibitors of cytochrome P-450-dependent arachidonic acid metabolism
AU - Capdevila, Jorge
AU - Gil, Lionel
AU - Orellana, Miriam
AU - Marnett, Lawrence J.
AU - Mason, J. Ian
AU - Yadagiri, Pendri
AU - Falck, J R
N1 - Funding Information:
i This work was supported by Grants USPHS GM 31278, GM 37922, and CA 30253, and the Robert A. Welch Foundation (I-782). 2 To whom correspondence should be addressed. 3 Abbreviations used: EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; ETYA, eicosatetraynoic acid; NDGA, nordihydroguaiaretic acid; BHT, butylated hydroxytoluene; BHA, butylated hydroxyanisole; PGH2, prostaglandin Hz; 5,6-
PY - 1988/3
Y1 - 1988/3
N2 - 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).
AB - 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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U2 - 10.1016/0003-9861(88)90340-2
DO - 10.1016/0003-9861(88)90340-2
M3 - Article
C2 - 3128168
AN - SCOPUS:0023866354
SN - 0003-9861
VL - 261
SP - 257
EP - 263
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -