Metabolism of [13C5] hydroxyproline in vitro and in vivo: implications for primary hyperoxaluria
Metabolism of [13C5] hydroxyproline in vitro and in vivo: implications for primary hyperoxaluria
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DOI：
10.1152/ajpgi.00331.2011
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发表时间：
2012-03-01
影响因子：
4.5
通讯作者：
Lowther, W. Todd
中科院分区：
文献类型：
--
作者：
Jiang, Juquan;Johnson, Lynnette C.;Lowther, W. Todd
姜军，约翰逊LC，骑士J，卡拉汉MF，里德尔·TJ，福尔摩斯RP，洛瑟·韦伯。[C-13(5)]羟脯氨酸在体外和体内的代谢：与原发性高草酸尿症的关系。Am J Physiol Gasterintest肝脏Physiol 302：G637-G643,2012。首次发表于2011年12月29日；doi：10.1152/ajpgi.00331.2011。-羟脯氨酸(Hyp)代谢是体内乙醛酸代谢的关键来源，可能是乙醛代谢受损的原发性高草酸尿症草酸过量产生的主要原因。我们知识中的重要空白包括识别具有降解Hyp能力的组织，以及研究这种代谢和如何抑制这种代谢的模型系统的发展。在15个不同的人体组织中检测了该途径中的酶的mRNA的表达。该完整通路在肝、肾、胰腺和小肠中均有表达。HepG2细胞也表达这些mRNAs和酶，并在培养液中将Hyp代谢为乙醇酸、甘氨酸和草酸。合成了[O-18]-和[C-13(5)]Hyp，并评价了它们在体外和体内模型中的应用。[O-18]Hyp不适合，因为[O-18]乙醛在烯醇和水合形式之间存在明显的互变互变，从而导致同位素的损失。[C-13(5)]Hyp则在体外和体内代谢为[C-13(2)]乙醇酸、[C-13(2)]甘氨酸和[C-13(2)]草酸。这些模型系统应该是探索Hyp代谢各个方面的有价值的工具，并将有助于确定阻断Hyp分解代谢是否是治疗原发性高草酸尿的有效疗法。
Jiang J, Johnson LC, Knight J, Callahan MF, Riedel TJ, Holmes RP, Lowther WT. Metabolism of [C-13(5)] hydroxyproline in vitro and in vivo: implications for primary hyperoxaluria. Am J Physiol Gastrointest Liver Physiol 302: G637-G643, 2012. First published December 29, 2011; doi:10.1152/ajpgi.00331.2011.-Hydroxyproline (Hyp) metabolism is a key source of glyoxylate production in the body and may be a major contributor to excessive oxalate production in the primary hyperoxalurias where glyoxylate metabolism is impaired. Important gaps in our knowledge include identification of the tissues with the capacity to degrade Hyp and the development of model systems to study this metabolism and how to suppress it. The expression of mRNA for enzymes in the pathway was examined in 15 different human tissues. Expression of the complete pathway was identified in liver, kidney, pancreas, and small intestine. HepG2 cells also expressed these mRNAs and enzymes and were shown to metabolize Hyp in the culture medium to glycolate, glycine, and oxalate. [O-18]-and [C-13(5)] Hyp were synthesized and evaluated for their use with in vitro and in vivo models. [O-18] Hyp was not suitable because of an apparent tautomerism of [O-18] glyoxylate between enol and hydrated forms, which resulted in a loss of isotope. [C-13(5)] Hyp, however, was metabolized to [C-13(2)] glycolate, [C-13(2)] glycine, and [C-13(2)] oxalate in vitro in HepG2 cells and in vivo in mice infused with [C-13(5)] Hyp. These model systems should be valuable tools for exploring various aspects of Hyp metabolism and will be useful in determining whether blocking Hyp catabolism is an effective therapy in the treatment of primary hyperoxaluria.