ENDOGENOUS BIOSYNTHESIS OF ARACHIDONIC-ACID EPOXIDES IN HUMANS - INCREASED FORMATION IN PREGNANCY-INDUCED HYPERTENSION
ENDOGENOUS BIOSYNTHESIS OF ARACHIDONIC-ACID EPOXIDES IN HUMANS - INCREASED FORMATION IN PREGNANCY-INDUCED HYPERTENSION
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DOI：
10.1073/pnas.87.15.5893
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发表时间：
1990-08-01
影响因子：
11.1
通讯作者：
FITZGERALD, GA
中科院分区：
文献类型：
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作者：
CATELLA, F;LAWSON, JA;FITZGERALD, GA
花生四烯酸通过P450同工酶代谢形成环氧二十碳三烯酸（E10）及其相应的二羟基衍生物（DH 10）。在本研究中，我们建立了人尿中8，9-，11，12-和14，15-雌二醇及其相应的脱氢酶的定量分析，并使用负离子，化学电离GC/MS和八氘内标。健康孕妇尿中8，9-和11，12-DHET的排泄量比非妊娠女性志愿者增加。相比之下，11，12-DHET和14，15-DHET的排泄，而不是8，9-DHET区域异构体，在妊娠高血压患者中甚至进一步增加。三条狗静脉注射[~ 3 H]~（14，15）-EET后，血浆中DHET明显升高。终末半衰期范围为7.9-12.3 min，分布容积（3.5-5.3 L）表明血浆室外分布有限。在尿液中检测到的放射性可忽略不计;这一事实推断，在生理情况下，尿液中的脱氢酶主要来源于肾脏。花生四烯酸的P450代谢产物在人体内形成，这支持了以下假设：这些代谢产物有助于对正常妊娠的生理反应和妊娠高血压的病理生理学。
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- and11,12-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.