CLIN.CHEM.40/9, 1686-1691 (1994) #{149} Laboratory Management and Utilization 1686 CLINICALCHEMISTRY,Vol.40, No. 9, 1994 Components of BiologicalVariation in Prolyl Endopeptidase and Dipeptidyl-Peptidase IV Activity in Plasma of Healthy Subjects Michael Maes,”6 Simon Scharp#{233},2 Ingrid De Meester,2 Philip Goossens,2 Annick Wauters,3 Hugo Neels,3 Robert Verkerk,2 Frans De Meyer,4 Peter D’Hondt,5 Dirk Peeters,5 Chris Schotte,5 and Paul Cosyns5 We investigated the components of biological variation in plasma prolyl endopeptidase (PEP; EC 3.4.21.26) and dipeptidyl-peptidase IV (DPP IV; EC 3.4.14.5) activity in healthy individuals. We took monthly blood samples from 26 healthy volunteers for determination of plasma PEP and DPP IV activity during one calendar year. The esti- mated CV5 for PEP activity were: total (CVJ = 25.0%, interindividual(CVg) = 13.9%, and intraindividual (CV1) = 16.8%. There was a statistically significant (P <0.0001) seasonal pattern in plasma PEP activity, with significantly higher values in the fall than in the other seasons. The peak-trough difference in the yearly variation in PEP ac- tivity, expressed as a percentage of the mean, was as high as 56.8%. The estimated CVs for DPP IV activity were: CV = 17.1%, CV9 = 14.5%, and CV, = 8.2%. DPP IV activity was significantly (P <0.0001) higher in summer than in the other seasons but the amplitude of the yearly variation was small. Indexing Terms: chronob y/peptidas s/variation, source of/ enzyme activity Prolyl endopeptidase (PEP, EC 3.4.21.26; post-proline cleaving enzyme; prolyl oligopeptidase) and dipeptidyl- peptidase W (DPP TV, EC 3.4.14.5) are widely distrib- uted among human tissues and body fluids (J_4)7 PEP is a cytosolic endopeptidase that cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass (1,2,5); DPP TV is a membrane- bound serine protease that catalyzes the cleavage of dipeptides from the amino terminus of polypeptides (6, 7). High PEP activity is observed in muscle, kidney, testes, submandibular gland, liver, thyroid, adrenal gland, thymus, and brain (1, 2). DPP TV activity has been localized in lung, liver, pancreas, peripheral blood mononuclear cells, and vascular endothelial cells (3). Both peptidases show substantial activity in human ‘Department of Psychiatry, Laboratory of Biological Psychia- try, Case Western Reserve University, Hanna Pavilion Rm. B-68, 2040 Abington Rd., Cleveland, OH 44106. 2Department of Medical Biochemistry, University of Antwerp, Antwerp, Belgium. 3Laboratory of Clinical Biology, Middelheim Ziekenhuis, Ant- werp, Belgium. 4Department of Geophysics, Royal Meteorological Institute, Brussels, Belgium. 5Department of Psychiatry, University Hospital of Antwerp, Belgium. 6Author for correspondence. Fax mt + 216-932-5254. 7Nonstandard abbreviations: PEP, prolyl endopeptidase; DPP N, dipeptidyl-peptidase N; ANOVA, analysis of variance; I-index, index of individuality; and PC, principal component. Received December 20, 1993; accepted April 28, 1994. serum or plasma (3, 4, 8), although the origin of PEP and DPP IV activity in blood remains elusive. Highly specific assays for determining PEP and DPP IV activity in blood have been described (3,4,8,9). Altered DPP IV activity has been found in several pathological condi- tions, including cancer (gastric, pancreatic, oral lympho- sarcoma, Hodgkin disease), hepatobiliary disorders, autoimmune disorders (rheumatoid arthritis, lupus erythematosus), and major depression (3, 10). Until now, only one pathological condition characterized by lower PEP serum activity has been reported: major de- pression (11). Both peptidases may play an important role in the regulation of cellular protein turnover and in processing and degradation of various peptide hor- mones, interleukins, and neuropeptides (8, 12, 13). However, the components of biological variation in the activity of both peptidases in the blood have not been established. Chronobiological research has re- vealed that many functions in healthy human beings are organized along a multifrequency time structure (14). For example, yearly rhythms may occur in various immune, endocrine, biochemical, and behavioral activ- ities (14). Our goal was to determine the interindivid- ual, intraindividual, and yearly variation in plasma PEP and DPP IV activity. Subjects and Methods Subjects This study was conducted around the city of Antwerp, Belgium (geographical coordinates, 51.2#{176}N, 4.5#{176}E). Healthy Caucasian volunteers were selected to partici- pate in this study. Inclusion criteria for subjects were: (a) physically and psychologically healthy; (b) living and working in an area <30 km from the Meteorological Station, Deurne, .Antwerp, Belgium; (c) a stable, settled lifestyle; and (d) usual reference values for blood tests, such as complete blood count, blood urea nitrogen, elec- trolytes, liver enzymes, hemoglobin, hematocrit, eryth- rocyte sedimentation rate, and thyroid function. Women of childbearing capability were included if they were certain not to become pregnant during the study. Sub- jects were excluded for past and current history of psy- chiatric disorders and personality disorders, which were assessed by means of the Semi-Structured Clinical In- terview described in the Diagnostic and Statistical Man- ual of Mental Disorders (15). The subjects were free of medical disorders (e.g., endocrine, immune, metabolic) and were taking no drugs (including oral contracep- tives). Subjects using or abusing drugs (alcohol and any other drugs of dependence) were not included. Subjects regularly taking international flights and subjects who