Patrignani P, Morton H, Cirino M, Lord A, Charette L, Gillard J, Rokach J, Patrono C
Merck Frosst Research Laboratories Pointe Claire-Dorval, Quebec, Canada.
Biochim Biophys Acta. 1989 Jul 21;992(1):71-7. doi: 10.1016/0304-4165(89)90052-4.
Following the intravenous administration of thromboxane (TX) B2, the stable hydration product of TXA2, to human and nonhuman primates the most abundant urinary metabolites are 2,3-dinor-TXB2 and 11-dehydro-TXB2. However, it is not known whether fractional conversion of TXB2 to its enzymatic metabolites is an accurate representation of TXA2 metabolism. Thus, we have compared the metabolic disposition of synthetic TXA2 and TXB2 via the beta-oxidation and 11-OH-dehydrogenase pathways in vivo in the monkey. TXA2 or TXB2 (20 ng/kg) was intravenously administered to four cynomolgus monkeys pretreated with aspirin in order to suppress endogenous TXA2 production. Urinary TXB2, 2,3-dinor-TXB2 and 11-dehydro-TXB2 were measured before, during and up to 24 h after thromboxane administration by means of reversed-phase high-performance liquid chromatography radioimmunoassay. Aspirin treatment suppressed urinary 2,3-dinor-TXB2 and 11-dehydro-TXB2 by approx. 75%. A similar fractional conversion of TXA2 and TXB2 into 2,3-dinor-TXB2 and 11-dehydro-TXB2 was found. These results suggest that TXA2 is hydrolyzed to TXB2 prior to enzymatic degradation and that metabolites of the latter represent reliable indices of TXA2 biosynthesis. Due to the variability in the conversion of thromboxanes into 2,3-dinor-TXB2 and 11-dehydro-TXB2, the measurement of both metabolites seems to represent a more reliable index of acute changes in TXA2 production.
在向人类和非人类灵长类动物静脉注射血栓素（TX）B2（TXA2的稳定水合产物）后，尿液中最丰富的代谢产物是2,3-二去甲-TXB2和11-脱氢-TXB2。然而，尚不清楚TXB2向其酶促代谢产物的分数转化率是否能准确反映TXA2的代谢情况。因此，我们比较了合成TXA2和TXB2在猴子体内通过β-氧化和11-羟基脱氢酶途径的代谢情况。向四只预先用阿司匹林处理以抑制内源性TXA2产生的食蟹猴静脉注射TXA2或TXB2（20 ng/kg）。在血栓素给药前、给药期间及给药后24小时内，通过反相高效液相色谱放射免疫分析法测定尿液中的TXB2、2,3-二去甲-TXB2和11-脱氢-TXB2。阿司匹林处理使尿液中的2,3-二去甲-TXB2和11-脱氢-TXB2减少了约75%。发现TXA2和TXB2转化为2,3-二去甲-TXB2和11-脱氢-TXB2的分数转化率相似。这些结果表明，TXA2在酶促降解之前先水解为TXB2，后者的代谢产物代表了TXA2生物合成的可靠指标。由于血栓素转化为2,3-二去甲-TXB2和11-脱氢-TXB2存在变异性，同时测量这两种代谢产物似乎是TXA2产生急性变化更可靠的指标。
