BERRY L J, SMYTHE D S
J Exp Med. 1963 Oct 1;118(4):587-603. doi: 10.1084/jem.118.4.587.
Cortisone is known to protect mice against the lethal effects of endotoxin. It also elevates liver tryptophan pyrrolase (TP) activity, an enzyme that converts tryptophan into an intermediate which, in turn, is transformed in a series of reactions into nicotinamide, a component of the pyridine nucleotides. In the present report, results of experiments attempting to link the prophylactic action of cortisone in endointoxication to metabolism of tryptophan are described. It was shown first that both nicotinamide and diphosphopyridine nucleotide (DPN), compounds along the pathway initiated by TP, are each as effective as cortisone in protecting mice against lethality of different amounts of endotoxin. L-Tryptophan, which alone results in an increase in liver TP, fails to protect against endotoxin when it is given either 4 hours before or concurrently with the toxin while it potentiates the toxin when administered 4 hours later. Cortisone, nicotinamide, and DPN all fail to protect mice against lethality when given 4 hours after endotoxin but they do not potentiate it as does tryptophan. Additional evidence linking tryptophan metabolism to endotoxin poisoning was derived from assays for TP. Activity of the enzyme in livers of mice 17 hours after injecting an LD(50) of endotoxin is less than one-half the control value. It remains below normal for 48 hours. In adrenalectomized mice, TP activity is about the same as in mice 17 hours after endotoxin. Animals protected against lethality of endotoxin by cortisone have normal levels of TP but if the cortisone is given 4 hours after the toxin, TP activity is the same as in mice given endotoxin alone. Tryptophan is unable to maintain a normal level of TP when it is given concurrently with endotoxin. TP activity is not depressed when mice made tolerant to endotoxin are given an injection of endotoxin at the LD(50) level for normal animals. Normal activity of the enzyme was always observed in livers of mice protected against endotoxin but not in those where protection failed. The total amount of oxidized pyridine nucleotides (PN(+)) in livers of mice 17 hours after an LD(60) of endotoxin is about two-thirds the normal level. Animals injected with either cortisone or nicotinamide at the same time as endotoxin maintain the PN(+) level in liver. Mice exposed to 5 degrees C during the postinjection period can be protected with cortisone or nicotinamide against lethality of endotoxin but not with DPN. Changes in TP activity do not parallel those found in mice kept at 25 degrees C. The toxic manifestations of endotoxin appear to be different, therefore, in animals stressed by cold.
已知可的松能保护小鼠免受内毒素的致死作用。它还能提高肝脏色氨酸吡咯酶（TP）的活性，该酶可将色氨酸转化为一种中间体，此中间体又会在一系列反应中转化为烟酰胺，而烟酰胺是吡啶核苷酸的一种成分。在本报告中，描述了试图将可的松在内毒素中毒中的预防作用与色氨酸代谢联系起来的实验结果。首先表明，烟酰胺和二磷酸吡啶核苷酸（DPN）这两种沿TP起始途径的化合物，在保护小鼠免受不同剂量内毒素致死方面与可的松一样有效。单独使用会使肝脏TP增加的L-色氨酸，在毒素注射前4小时或与毒素同时给药时不能保护小鼠免受内毒素侵害，而在毒素注射4小时后给药则会增强毒素的作用。在内毒素注射4小时后给予可的松、烟酰胺和DPN，均不能保护小鼠免受致死作用，但它们不会像色氨酸那样增强致死作用。将色氨酸代谢与内毒素中毒联系起来的其他证据来自对TP的测定。注射致死剂量（LD）50的内毒素17小时后，小鼠肝脏中该酶的活性不到对照值的一半。在48小时内一直低于正常水平。在肾上腺切除的小鼠中，TP活性与注射内毒素17小时后的小鼠大致相同。用可的松保护免受内毒素致死的动物TP水平正常，但如果在毒素注射4小时后给予可的松，TP活性与仅注射内毒素的小鼠相同。当色氨酸与内毒素同时给药时，它无法维持TP的正常水平。当对内毒素产生耐受性的小鼠注射正常动物LD50水平的内毒素时，酶的活性并未降低。在免受内毒素保护的小鼠肝脏中总是观察到该酶的正常活性，而在保护失败的小鼠肝脏中则未观察到。注射致死剂量（LD）60的内毒素17小时后，小鼠肝脏中氧化吡啶核苷酸（PN(+)）的总量约为正常水平的三分之二。与内毒素同时注射可的松或烟酰胺的动物，肝脏中的PN(+)水平得以维持。注射后期间暴露于5摄氏度的小鼠，可用可的松或烟酰胺保护免受内毒素致死，但不能用DPN保护。TP活性的变化与在25摄氏度饲养的小鼠中发现的变化不平行。因此，在内毒素的毒性表现上，受寒冷应激的动物似乎有所不同。
