Emmett Michael
Division of Nephrology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas.
Clin J Am Soc Nephrol. 2014 Jan;9(1):191-200. doi: 10.2215/CJN.07730713. Epub 2013 Nov 14.
The acquired form of 5-oxoproline (pyroglutamic acid) metabolic acidosis was first described in 1989 and its relationship to chronic acetaminophen ingestion was proposed the next year. Since then, this cause of chronic anion gap metabolic acidosis has been increasingly recognized. Many cases go unrecognized because an assay for 5-oxoproline is not widely available. Most cases occur in malnourished, chronically ill women with a history of chronic acetaminophen ingestion. Acetaminophen levels are very rarely in the toxic range; rather, they are usually therapeutic or low. The disorder generally resolves with cessation of acetaminophen and administration of intravenous fluids. Methionine or N-acetyl cysteine may accelerate resolution and methionine is protective in a rodent model. The disorder has been attributed to glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle. However, the specific metabolic derangements that cause the 5-oxoproline accumulation remain unclear. An ATP-depleting futile 5-oxoproline cycle can explain the accumulation of 5-oxoproline after chronic acetaminophen ingestion. This cycle is activated by the depletion of both glutathione and cysteine. This explanation contributes to our understanding of acetaminophen-induced 5-oxoproline metabolic acidosis and the beneficial role of N-acetyl cysteine therapy. The ATP-depleting futile 5-oxoproline cycle may also play a role in the energy depletions that occur in other acetaminophen-related toxic syndromes.
5-氧代脯氨酸（焦谷氨酸）代谢性酸中毒的后天获得形式于1989年首次被描述，次年提出了其与长期服用对乙酰氨基酚的关系。从那时起，这种慢性阴离子间隙代谢性酸中毒的病因得到了越来越多的认识。许多病例未被识别，因为5-氧代脯氨酸的检测方法尚未广泛应用。大多数病例发生在有长期服用对乙酰氨基酚病史的营养不良、慢性病女性中。对乙酰氨基酚水平很少处于中毒范围；相反，它们通常是治疗剂量或较低剂量。该病症通常在停用对乙酰氨基酚并给予静脉补液后缓解。蛋氨酸或N-乙酰半胱氨酸可能会加速缓解，并且蛋氨酸在啮齿动物模型中具有保护作用。该病症被认为与谷胱甘肽耗竭和γ-谷氨酰循环中一种关键酶的激活有关。然而，导致5-氧代脯氨酸积累的具体代谢紊乱仍不清楚。一个消耗ATP的无效5-氧代脯氨酸循环可以解释长期服用对乙酰氨基酚后5-氧代脯氨酸的积累。这个循环由谷胱甘肽和半胱氨酸的耗竭激活。这一解释有助于我们理解对乙酰氨基酚诱导的5-氧代脯氨酸代谢性酸中毒以及N-乙酰半胱氨酸治疗的有益作用。消耗ATP的无效5-氧代脯氨酸循环也可能在其他与对乙酰氨基酚相关的毒性综合征中发生的能量消耗中起作用。
