Changes in hepatic metabolic enzyme activities and biliary excretion of 4-nitrophenol in streptozotocin induced diabetic rats

Abstract Activity of hepatic metabolic enzymes of glucuronidation and sulfation of 4-nitrophenol (PNP) and biliary excretion of its glucuronide (PNP-G) and sulfate (PNP-S) conjugates have been investigated in control and streptozotocin (STZ)-induced diabetic rats. 500 μM PNP solution was luminally perfused in a cannulated jejunal loop for 90 minutes. It was found that biliary excretion of PNP-G was significantly decreased in the diabetic rats. This effect of STZ could be completely reversed by administration of rapid-acting insulin. Activity of hepatic UDP-glucuronyltransferase and β-glucuronidase was also depressed by the STZ pretreatment. Administration of insulin antagonized the inhibitory action of STZ on UDP-glucuronyltransferase, but the reduced activity of β-glucuronidase was not reversed. Biliary excretion of PNP-S was also depressed in the diabetic rats. Whereas, different effects of insulin administration were observed. Namely, the lower biliary excretion rate of PNP-S was not changed after administration of insulin. Activity of the sulfotransferase and the arylsulfatase enzymes was not altered either by STZ pretreatment or by insulin administration. Biliary excretion of PNP was also significantly depressed by STZ and this depression was not changed after insulin administration. The results call attention to hepatobiliary circulation of low molecular weight xenobiotics and their glucuronide and sulfate conjugates.

摘要：本研究针对对照组及链脲佐菌素（streptozotocin, STZ）诱导的糖尿病大鼠，探究了对硝基苯酚（4-nitrophenol, PNP）的葡萄糖醛酸化与硫酸化肝脏代谢酶活性，及其葡萄糖醛酸结合物（PNP-G）与硫酸酯结合物（PNP-S）的胆汁排泄情况。实验采用插管空肠袢腔内灌流500 μM的PNP溶液，持续灌注90分钟。结果发现，糖尿病大鼠的PNP-G胆汁排泄量显著降低，该STZ诱导的效应可通过速效胰岛素给药完全逆转。STZ预处理还可抑制肝脏UDP-葡萄糖醛酸转移酶（UDP-glucuronyltransferase）与β-葡萄糖醛酸苷酶（β-glucuronidase）的活性；胰岛素给药可拮抗STZ对UDP-葡萄糖醛酸转移酶的抑制作用，但无法逆转β-葡萄糖醛酸苷酶活性的降低。糖尿病大鼠的PNP-S胆汁排泄量同样受到抑制，而胰岛素给药对此未产生明显干预效果，即给药后PNP-S较低的胆汁排泄速率并未发生改变。磺基转移酶（sulfotransferase）与芳基硫酸酯酶（arylsulfatase）的活性既不受STZ预处理影响，也不会因胰岛素给药发生变化。此外，STZ还可显著降低PNP的胆汁排泄，且该抑制效应不会因胰岛素给药得到改善。本研究结果提醒学界关注低分子量外源性物质及其葡萄糖醛酸、硫酸酯结合物的肝胆循环过程。