Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo
Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo
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DOI：
10.1074/jbc.m105854200
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发表时间：
2001-10-05
影响因子：
4.8
通讯作者：
Marnett, LJ
中科院分区：
文献类型：
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作者：
Kozak, KR;Crews, BC;Marnett, LJ
前列腺素甘油酯（PG-Gs）和前列腺素乙醇酰胺（PG-EAs）分别由环加氧酶-2作用于内源性大麻素2-花生四烯基甘油（2-AG）和花生四烯基乙醇酰胺生成。这些新型类二十烷酸可能具有独特的药理学性质和/或作为前列腺素的潜在来源，远离其起源组织。因此，我们在体外和体内研究了PG-Gs和PG-EAs的代谢。PGE(2)-G在大鼠血浆中迅速水解生成PGE(2) (t(1/2) = 14 s)，但在人血浆中代谢缓慢（t(1/2) bb0 10 min）。在人全血中观察到PGE(2)-G有中等程度的代谢（t(1/2)，约为7 min）。母体花生四烯酰基甘油2-AG和更稳定的区域异构体1-AG在大鼠血浆中的代谢速度也比人血浆快得多。PGE(2)-EA在血浆中没有明显水解，经过缓慢的脱水/异构化成PGB(2)-EA。PGE(2)-G和PGE(2)-EA在犬、牛和人脑脊液中均稳定存在。人15-羟基前列腺素脱氢酶是体内PG失活的第一步，它对PGE(2)-G和PGE(2)-EA的氧化效率低于游离酸。位阻甘油前列腺素是E系列中最差的底物。观察到最小的15-羟基前列腺素脱氢酶氧化PGF(2 α)-G。测定PGE(2)-G和PGE(2)-EA在大鼠体内的药代动力学。静脉给药2 mg/kg后5分钟血浆中未检出PGE(2)-G。然而，PGE(2)-EA在相同剂量后2小时内仍可检测到，显示出较大的表观体积分布和超过6分钟的半衰期。结果表明，内源性大麻素衍生的pg样化合物在人体中可能足够稳定，可以发挥全身作用。此外，这些结果表明，大鼠不是研究2-花生四烯酰基甘油或甘油前列腺素在人体内生物活性的适当模型。
Prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs) are generated by the action of cyclooxygenase-2 on the endocannabinoids 2-arachidonylglycerol (2-AG) and arachidonylethanolamide, respectively. These novel eicosanoids may have unique pharmacological properties and/or serve as latent sources of prostaglandins at sites remote from their tissue of origin. Therefore, we investigated the metabolism of PG-Gs and PG-EAs in vitro and in vivo. PGE(2)-G was rapidly hydrolyzed in rat plasma to generate PGE(2) (t(1/2) = 14 s) but was only slowly metabolized in human plasma (t(1/2) > 10 min). An intermediate extent of metabolism of PGE(2)-G was observed in human whole blood (t(1/2) approximate to 7 min). The parent arachidonylglycerol, 2-AG, and the more stable regioisomer, 1-AG, also were much more rapidly metabolized in rat plasma compared with human plasma. PGE(2)-EA was not significantly hydrolyzed in plasma, undergoing slow dehydration/isomerization to PGB(2)-EA. Both PGE(2)-G and PGE(2)-EA were stable in canine, bovine, and human cerebrospinal fluid. Human 15-hydroxyprostaglandin dehydrogenase, the enzyme responsible for the initial step in PG inactivation in vivo, oxidized both PGE(2)-G and PGE(2)-EA less efficiently than the free acid. The sterically hindered glyceryl prostaglandin was the poorest substrate examined in the E series. Minimal 15-hydroxyprostaglandin dehydrogenase oxidation of PGF(2 alpha)-G was observed. PGE(2)-G and PGE(2)-EA pharmacokinetics were assessed in rats. PGE(2)-G was not detected in plasma 5 min following an intravenous dose of 2 mg/kg. However, PGE(2)-EA was detectable up to 2 h following an identical dose, displaying a large apparent volume of distribution and a half-life of over 6 min. The results suggest that endocannabinoid-derived PG-like compounds may be sufficiently stable in humans to exert actions systemically. Furthermore, these results suggest that the rat is not an adequate model for investigating the biological activities of 2-arachidonylglycerol or glyceryl prostaglandins in humans.