Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo.
Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo.
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发表时间：
1992-03
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通讯作者：
S. Ahmad;Lianguo Wang;P. Ward
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作者：
S. Ahmad;Lianguo Wang;P. Ward
最近的研究表明，日本Charles River Inc.特别缺乏二肽基（氨基）肽酶IV（DAP IV-阴性; EC 3.4.14.5），而来自美国的Fischer-344大鼠（DAP IV-阳性）具有正常的DAP IV活性。在本研究中，DAP IV阳性大鼠的血浆通过血管紧张素转换酶（EC 3.4.15.1）（1.86 +/- 0.50 nmol/min/ml）和DAP IV（2.56 +/- 0.42 nmol/min/ml）代谢P物质（SP）（5.37 +/- 0.25 nmol/min/ml）。DAP IV依次将SP转换为SP[3-11]和SP[5-11]。然后SP[5-11]代谢物被血浆氨肽酶M（AmM; EC 3.4.11.2）快速水解（36.2 +/- 4.2 nmol/min/ml）。相比之下，由于完全缺乏DAP IV水解，DAP IV阴性大鼠血浆中的SP代谢不到对照动物的一半（2.14 +/- 0.06 nmol/min/ml）。不存在DAP IV与血管紧张素转化酶介导的SP水解（1.45 +/- 0.11 nmol/min/ml）或AmM介导的SP水解[5-11]（37.1 +/- 0.9 nmol/min/ml）的任何差异无关。与SP代谢的这种缺陷相一致，与DAP IV阳性动物相比，SP在体内刺激DAP IV阴性大鼠的唾液分泌更有效。增强是特异性的，因为SP[5-11]，一种对DAP IV具有抗性的SP片段，在DAP IV阴性和阳性动物中是等效的。当AmM介导的水解被amastatin（20 nmol/min，i. v.）抑制时，SP[5-11]诱导的唾液分泌在两种菌株中均增强。这些数据为DAP IV和AmM在SP和活性SP代谢物的体内加工中的重要作用提供了直接证据。
Recent studies have demonstrated that Fischer-344 rats from Japanese Charles River Inc. specifically lack dipeptidyl(amino)peptidase IV (DAP IV-negative; EC 3.4.14.5), whereas Fischer-344 rats from sources within the United States (DAP IV-positive) possess normal DAP IV activity. In the present study, plasma from DAP IV-positive rats metabolized substance P (SP) (5.37 +/- 0.25 nmol/min/ml) via the actions of angiotensin-converting enzyme (EC 3.4.15.1) (1.86 +/- 0.50 nmol/min/ml) and DAP IV (2.56 +/- 0.42 nmol/min/ml). DAP IV sequentially converted SP to SP[3-11] and SP[5-11]. The SP[5-11] metabolite was then rapidly hydrolyzed by plasma aminopeptidase M (AmM; EC 3.4.11.2) (36.2 +/- 4.2 nmol/min/ml). In contrast, SP metabolism by plasma from DAP IV-negative rats was less than half that of control animals (2.14 +/- 0.06 nmol/min/ml), due to a complete lack of DAP IV hydrolysis. The absence of DAP IV was not associated with any differences in angiotensin-converting enzyme-mediated hydrolysis of SP (1.45 +/- 0.11 nmol/min/ml) or AmM-mediated hydrolysis of SP[5-11] (37.1 +/- 0.9 nmol/min/ml). Consistent with this deficiency in SP metabolism, SP was more potent in vivo in stimulating salivary secretion in DAP IV-negative rats compared to DAP IV-positive animals. Potentiation was specific in that SP[5-11], an SP fragment resistant to DAP IV, was equipotent in DAP IV-negative and positive animals. SP[5-11]-induced salivary secretion was potentiated in both strains when AmM-mediated hydrolysis was inhibited by amastatin (20 nmol/min, i.v.). These data provide direct evidence for a significant role for DAP IV and AmM in the in vivo processing of SP and active SP metabolites.