油酸盐对苯并[A]芘酚葡萄糖醛酸化抑制的作用机理

Mechanisms of inhibitory effect of oleate on glucuronidation of benzolalpyrene phenols

利用肝脏灌流模型及肝脏微粒体对油酸影响羟基苯并[a]芘葡萄糖醛酸化的机理进行了研究,结果表明,低剂量的油酰辅酶A可非竞争性地抑制大鼠肝微粒体UDP-葡萄醛酰转移酶的活性,使3-羟基苯并芘葡萄糖醛酰化作用受抑制,牛血清白蛋白与Triton X-100可促进油酰辅酶A对转移酶的抑制作用。 600 μmol·L^(-1)的油酸灌流肝脏,可使肝脏中UDPGA,UDPG及ATP分别下降44％,49％及44％,因此高剂量的油酸亦可通过改变辅因子供应而抑制羟基苯并芘的葡萄糖醛酸化过程。 250μmol·L^(-1)的油酸灌流缺乏β-葡萄糖醛酸酶的C_3H/He小鼠肝脏,可使流出液中游离羟基苯并芘增加136％,而与葡萄糖醛酸结合的羟基苯并芘减少了32％,同时肝脏中与葡萄糖醛酸结合的羟基苯并芘减少64％,以油酸灌流具有高β-葡萄糖醛酸酶的DBA/2小鼠肝脏可见同样改变,在肝脏微粒体的实验中亦未见油酰辅酶A对苯并芘-0-葡萄糖醛酸的水解作用有何影响,据此,油酸对羟基苯并芘葡萄醛酸化状态的影响与β-葡萄糖醛酸酶无关。

The purpose of this study was to investigate the mechanisms by which oleate influences the glucuronidation of benzo[a]pyrene phenols [BP-P] in the isolated microsomes and perfused liver.Low doses of oleoyl CoA inhibited UDP glucuronyl transferase [UDPG-T] non-competitively in the isolated rat microsomes with 3-hydroxy-benzopyrene [3-OH-BP] as the substrate. Albumin and Triton X-100 enhanced the inhibition of the transferase by oleoyl CoA.Infusion of oleate (600μmol·L-1) decreased the hepatic contents of UDP-glucuronic acid (UDPGA), UDP-glucose (UDPG) and ATP by 44, 49 and 44% respectively. Thus, oleate might inhibit glucuronidation by altering cofactor supply at the high concentration.In the β-glucuronidase deficient C3H / He mice, infusion of oleate (250 μmol·L-1) increased the release of free BP-P by 136% and decreased the release of glucuronides by 32% in the perfusate. Concomitantly, storages of glucuronides in the liver were diminished by 64%. A similar tendency was observed in DBA / 2 mice with highβ-glucuronidase level. Rates of hydrolysis of benzo[a]pyrene-0 glucuronides [BP-G] were not altered by oleoyl CoA in the isolated rat microsomes. Therefore, oleate does not alter glucuronidation by acting on β-glucuroni-dase.