Johnston T P, Palmer W K
Department of Pharmaceutics, College of Pharmacy, University of Illinois at Chicago 60612.
Biochem Pharmacol. 1993 Sep 14;46(6):1037-42. doi: 10.1016/0006-2952(93)90668-m.
One 300 mg i.p. injection of the nonionic surfactant poloxamer 407 (Pluronic F-127) produces a significant increase above control of both circulating cholesterol and triglyceride (TG) concentrations. The present study was conducted to determine the effect of poloxamer 407 (P-407) on the capacity to hydrolyze circulating TG by lipoprotein lipase (LPL) in an attempt to determine the mechanism of action of P-407. The concentration of TG in the rat following a single 300 mg i.p. injection of P-407 was marked, increasing from 84 +/- 10 to 3175 +/- 322 mg/dL at 24 hr. The maximal rate of TG accumulation (5.74 mg/dL/min) in the plasma of P-407-injected rats occurred between 2 and 4 hr post-injection. In vitro incubation of LPL with P-407 significantly inhibited enzyme activity with an inhibitory concentration at which 50% of the enzymatic activity was lost of approximately 24 microM. Concentrations of P-407 exceeding 350 microM in vitro completely inhibited LPL activity. The effects of P-407 on the enzymatic activity of LPL in post-heparin plasma obtained following a single 300 mg dose of P-407 to rats demonstrated greater than 95% suppression of LPL activity 3 hr post-injection compared with controls. Inhibition of LPL activity was greater than 90% as long as 24 hr following a single i.p. injection of P-407. However, while the heparin-releasable fraction of capillary-bound LPL was inhibited in the plasma, LPL activity significantly increased in cardiac and skeletal muscle in poloxamer-injected animals compared with sham-injected controls. Although there was no significant change in LPL activity in adipose tissue, testes, and lung resulting from P-407 treatment, LPL activity increased by 37% in myocardium, 69% in soleus, and 66% in gastrocnemius muscle in P-407-injected rats when compared with controls. Our studies would suggest that the predominant mechanism by which P-407 induced an increase in circulating TG was by a reduction in the rate at which TG was hydrolyzed due to inhibition of heparin-releasable LPL by the surfactant.
腹腔注射300毫克非离子表面活性剂泊洛沙姆407（普朗尼克F - 127）会使循环胆固醇和甘油三酯（TG）浓度显著高于对照组。本研究旨在确定泊洛沙姆407（P - 407）对脂蛋白脂肪酶（LPL）水解循环TG能力的影响，以试图确定P - 407的作用机制。大鼠腹腔注射单次300毫克P - 407后，TG浓度显著升高，在24小时时从84±10毫克/分升增至3175±322毫克/分升。注射P - 407的大鼠血浆中TG积累的最大速率（5.74毫克/分升/分钟）出现在注射后2至4小时之间。LPL与P - 407的体外孵育显著抑制酶活性，使50%酶活性丧失的抑制浓度约为24微摩尔。体外P - 407浓度超过350微摩尔时完全抑制LPL活性。对大鼠单次注射300毫克P - 407后获取的肝素后血浆中，P - 407对LPL酶活性的影响显示，注射后3小时与对照组相比，LPL活性抑制超过95%。单次腹腔注射P - 407后长达24小时，LPL活性抑制均大于90%。然而，虽然血浆中与毛细血管结合的肝素可释放部分LPL受到抑制，但与假注射对照组相比，泊洛沙姆注射动物的心脏和骨骼肌中LPL活性显著增加。尽管P - 407处理后脂肪组织、睾丸和肺中的LPL活性无显著变化，但与对照组相比，注射P - 407的大鼠心肌中LPL活性增加37%，比目鱼肌中增加69%，腓肠肌中增加66%。我们的研究表明，P - 407诱导循环TG增加的主要机制是由于表面活性剂抑制肝素可释放LPL，从而降低了TG的水解速率。
