Selective inhibition of arachidonic acid epoxidation in vivo.
Cytochrome P450 (CYP)-derived arachidonic acid metabolites, including epoxyeicosatrienoic acids (EETS) and 20-HETE, have been implicated in the regulation of renal function and vascular tone. Studying the function of specific CYP arachidonate metabolites has been hampered due to lack of selective inhibitors and difficulty in their solubilization. We have identified MS-PPOH as a potent and selective inhibitor of CYP-catalyzed arachidonate epoxidation in vitro. We used 2-hydroxypropyl-beta-cyclodextrin as a vehicle in order to administer MS-PPOH in vivo. One hour after administration, MS-PPOH (5 mg, IV bolus) significantly inhibited arachidonic acid epoxidation in rat renal cortical microsomes (vehicle-282 +/- 12 pmol/mg/min, MS-PPOH-206 +/- 10 pmol/mg/min, p < 0.05) but had no effect on 20-HETE formation (vehicle-383 32 pmol/mg/min, MS-PPOH-367 +/- 9 pmol/mg/min). The inhibitory effect lasts at least for 6 hours. There was no inhibition of 20-HETE synthesis at any time point. We also examined the effect of MS-PPOH on renal excretiry function. Three hours after MS-PPOH administration to anesthetized rats, urine flow rate became significantly higher (vehicle-275 +/- 16 microl/hour, MS-PPOH-406 +/- 44 microl/hour, p < 0.05). Sodium excretion rate was also significantly higher (vehicle-28.7 +/- 4 micromol/hour, MS-PPOH-63.3 +/- 10 micromol/hour, p < 0.05) but potassium excretion rate was not affected (vehicle-65.5 +/- 5 micromol/hour, MS-PPOH-79.2 +/- 2 micromol/hour). These results suggest that MS-PPOH may be useful as a selective inhibitor of CYP-catalyzed arachidonic acid epoxidation in vivo, and implicate EETs and anti-diuretic and anti-natriuretic in the regulation of renal function.
Brand-Schieber
E
E
Department of Pharmacology, New York Medical College, Valhalla, USA.
Falck
J F
JF
Schwartzman
M
M
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000502:physiology; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology
D000577:Amides; D003505:Cyclodextrins; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D013450:Sulfones; C074765:propenylphosphonic acid; D016718:Arachidonic Acid; C047008:17-octadecynoic acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D015126:8,11,14-Eicosatrienoic Acid