Endogenous biosynthesis of arachidonic acid epoxides in humans: increased formation in pregnancy-induced hypertension.
Arachidonic acid is metabolized by means of P450 isoenzyme(s) to form epoxyeicosatrienoic acids (EETs) and their corresponding dihydroxy derivatives (DHETs). In the present study, we established the presence in human urine of 8,9-, 11,12-, and 14,15-EETs and their corresponding DHETs by developing quantitative assays and using negative ion, chemical ionization GC/MS and octadeuterated internal standards. Urinary excretion of 8,9- and 11,12-DHET increased in healthy pregnant women compared with nonpregnant female volunteers. By contrast, excretion of 11,12-DHET and 14,15-DHET, but not the 8,9-DHET regioisomer, increased even further in patients with pregnancy-induced hypertension. Intravenous administration of [3H]14,15-EET to three dogs markedly increased its DHET in plasma. The terminal half-life ranged from 7.9-12.3 min and the volume of distribution (3.5-5.3 liters) suggested limited distribution outside the plasma compartment. Negligible radioactivity was detected in urine; this fact infers that under physiological circumstances, urinary DHETs largely derive from the kidney. That P450 metabolites of arachidonic acid are formed in humans supports the hypothesis that these metabolites contribute to the physiological response to normal pregnancy and the pathophysiology of pregnancy-induced hypertension.
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232.
F
F
Catella
J A
JA
Lawson
D J
DJ
Fitzgerald
G A
GA
FitzGerald
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine*; D000818:Animals; D004285:Dogs; D005231:Fatty Acids, Unsaturated / Q000652:urine*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000652:urine; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000378:metabolism*; D011865:Radioisotope Dilution Technique; D012016:Reference Values; D014316:Tritium
D005231:Fatty Acids, Unsaturated; D014316:Tritium; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid