Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo.
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.
Department of Physiology, College of Medicine, Ohio State University.
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Ahmad
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Wang
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Ward
D000626:Aminopeptidases / Q000502:physiology*; D000818:Animals; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000502:physiology*; D005260:Female; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D013373:Substance P / Q000378:metabolism*
D010446:Peptide Fragments; D013373:Substance P; C031661:substance P (5-11); D000626:Aminopeptidases; D018826:CD13 Antigens; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4