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A Bombesin Immunoreactive Peptidein Milk

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A Bombesin Immunoreactive Peptidein Milk Proc. Natl. Acad. Sci. USA Vol. 81, pp. 578-582, January 1984 Medical Sciences A bombesin immunoreactive peptide in milk (radioinimunoassay/gel filtration/high-performance liquid chromatography) GLORIA D. JAHNKE* AND LAWRENCE H. LAZARUSt Peptide Neurochemistry Workgroup, Laboratory of Behavioral and Neurological Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 Communicated by George H. Hitchings, September 19, 1983 ABSTRACT Immunoreactivity to the amphibian peptide tains peptide and steroid hormones (32), prostaglandins (33), bombesin was found in instant nonfat dry milk (ca. 0.7 ng/ml) morphine (34), melatonin (35), and immunoglobulins (36) in and in the whey of whole or skim bovine milk (ca. 1.2 ng/ml) addition to a growth factor and enzymes (37, 38). even after ultracentrifugation. The soluble immunoreactivity Moreover, the peptide hormones and the growth factor re- was associated with a peptide exhibiting the following charac- tain their biological activities in milk (37, 39, 40) and, when teristics: (i) parallel displacement in an immunoassay using an ingested by the neonate, appear intact in plasma (35, 39-42). antiserum recognizing bombesin amino acid residues 5-8; (ii) Thus, considering the coincidence between the action of am- separation from both gastrin-releasing peptide and amphibian phibian bombesin and milk on hormone peptide levels, we bombesin by gel filtration-the approximate Mr was 3,200; sought to determine whether milk could be a source of a (iii) denaturation in urea, reduction by dithiothreitol, and bombesin-related peptide. In this communication, we pro- acetylation by iodoacetamide had no effect on its elution profile vide evidence that milk contains bombesin immunoreactivity by gel-filtration chromatography and the aggregation of added that is distinct from both GRP and amphibian bombesin and bombesin to milk proteins or peptides was not observed; (iv) is associated with a heat-stable, protease-sensitive peptide reversed-phase HPLC separated milk immunoreactivity from with a Mr of about 3,200. gastrin-releasing peptide and bombesin; (v) digestion by tryp- sin yielded a smaller immunoreactive peptide fragment, MATERIALS AND METHODS whereas nearly all immunoreactivity was lost by treatment and whole milk from several differ- with a-chymotrypsin; and (vi) the level of immunoreactivity Milk. Pasteurized skim milk is an ent local dairies were purchased 5-7 days before the expira- was unaffected by boiling. These data show that tion date. Instant nonfat dry milk was the product of several exogenous source of bombesin-like immunoreactivity,, which reconstituted according to the manu- may account for the increase of gastric acid and gastrointesti- major companies and of milk. facturer. A portion (200 ml) was acidified to pH 2.3 with for- nal hormone levels after the consumption mic acid and brought to 80% in cold acetone according to Brown et al. (2) for the extraction of bombesin from plasma. Immunoreactivity to bombesin, an amphibian tetradecapep- The extract was clarified by centrifugation (20,000 x g for 30 tide (1), is distributed throughout mammalian tissues (2-5). min at 40C), and the supernatant was decreased in volume Bombesin administered through intraperitoneal or intracis- under vacuum and clarified again by centrifugation. The vol- ternal injection or intravenous infusion elicits diverse phys- ume of this supernatant was then further decreased under iological effects in a variety of animal species, including hu- nitrogen at 500C. mans (6-12). These effects include hypertension (1, 6, 13, Radioimmunoassay (RIA). [Tyr8]Bombesin and GRP were 14), satiety (for review, see ref. 15), change in sugar metabo- iodinated every 4-6 weeks as described (43). The production lism (16, 17), hypothermia (18), modulation of the level of of the antiserum to bombesin has been described (44). Op- many gastrointestinal-associated peptide hormones (6-12, timum RIA conditions, which were systematically deter- 19-24), and increase of gastric acid secretion (7, 10, 13, 14, mined, are as follows: 0.1 M sodium cacodylate, pH 5.6/bo- 19, 20). Bombesin also releases both gastrin and gastric acid in vine serum albumin (5 mg/ml)/125I-labeled [Tyr8]bombesin from isolated fundic mucosa (25) and acts as a spasmogen (or GRP) (2,500 cpm)/antiserum BM-XII-165-4 (final dilu- isolated smooth muscle preparations (1, 6, 13, 14, 26). In tion, 1:4,000)/standard or test solution in a total vol of 100 keeping with these observations, specific bombesin-contain- ,ul. Nonionic (Triton X-100, Nonidet P-40) and ionic (sodium ing cells were identified by immunohistochemistry in the lauryl sulfate) detergents above 0.1% and chaotropic agents gastric mucosa (27). Furthermore, an endogenous bombesin- (urea, guanidine HCl) above 0.1 M substantially decreased like gastrin-releasing peptide (GRP) was isolated from mam- binding of the labeled peptide to the antibody. The antibody- malian non-antral tissue (28), and its pharmacological mode bound ligand was precipitated after a 16-18 hr incubation at of action is similar to bombesin at comparable dosages (17, 40C with 1.0 ml of 15.6% polyethylene glycol 8000 in the 24, 27, 29). presence of 0.05 ml of outdated human plasma (44). Based Infusion of bombesin brings about an increase above basal on the relative crossreactivity of sequence-related peptides plasma levels of the peptide hormones insulin, gastrin-inhib- (Table 1) this antiserum apparently recognizes the mid-re- iting peptide, neurotensin, pancreatic polypeptide, gastrin, gion of bombesin (residues 5-8). The oxidation of trypto- motilin, enteroglucagon, secretin, and growth hormone (6- phan-8 also decreased binding of bombesin to the antibody. 14, 19-23); these are the same peptides that increase after Alytesin, used as the amphibian analogue of chicken proven- the consumption of milk in human neonates (for review, see tricular GRP (45), and porcine GRP produced nonparallel ref. 30). Bombesin also increases the levels of somatostatin displacement curves relative to bombesin (Fig. 1). Other (22) and prolactin (9). Milk, which is a rich nutrient meal, is known peptides, such as physalaemin, neurotensin, and bra- known for its caloric components (protein, carbohydrates, it also con- fat) and micronutrients (vitamins, minerals) (31); Abbreviations: RIA, radioimmunoassay; GRP, gastrin-releasing peptide (bombesin-like heptacosapeptide). The publication costs of this article were defrayed in part by page charge *Present address: School of Veterinary Medicine, North Carolina payment. This article must therefore be hereby marked "advertisement" State University, Raleigh, NC 27650. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 578 Downloaded by guest on September 24, 2021 Medical Sciences: Jahnke and Lazarus Proc. Natl. Acad Sci. USA 81 (1984) 579 Table 1. Specificity of antiserum to bombesin Relative molar Peptide Structure crossreactivity Bombesin pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 1.00 [Tyr']Bombesin Tyr 1.00 [Tyr8]Bombesin Tyr 0.73 [Tyr5]Bombesin-(5-14) Tyr 0.18* Alytesin Gly Thr 2.62 ± 0.87 (5)* GRPt -Met-Tyr-Pro-Arg His 1.34 ± 0.14 (6)* Ranatensin pGlu-Val-Pro Phe 0.0003 Litorin pGlu Phe 0.0008 Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly 0.000003 Peptide concentrations ranged from 0.1 fmol/ml to 1.3 nmol/ml. Relative molar crossreactivity is based on 50% displacement point from log- logit plots; n value in parentheses when more than two repetitions. *Nonparallel displacement curves. tThe sequence of porcine GRP preceding the bombesin-like region is Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys- (28). dykinin failed to displace the radioligand at concentrations of RESULTS 10 nmol/ml. Quantitation. Whole, skim, and reconstituted dry bovine Chromatography. Gel filtration of milk extracts used Bio- milk, whey, and the acid/acetone extract produced displace- Gel P-4 (100-200 mesh) columns (1.5 x 94 cm) equilibrated ment curves in the RIA parallel to that of bombesin (Fig. 2). with 0.1 M formic acid. The immunoreactive peak from this To rule out the possibility that the bombesin immunoreactiv- column fractionation was concentrated, absorbed onto and ity could be extracted by formic acid from a bacterial con- eluted from a Sep-Pak with methanol, and injected onto a taminant [Escherichia coli has been found to contain insu- reversed-phase HPLC system [Laboratory Data Control unit lin (47)], lipids, or leukocytes (38), milk was centrifuged fitted with a Rheodyne injector with a Spherisorb ODS 5-gm (100,000 x g for 30 min at 4°C) before assaying; the displace- (250 x 4.6 mm) or a Bio-Sil ODS 5-,um (150 x 4 mm, end- ment curve of the resultant whey was superimposable on capped) column]. The samples were eluted with linear gradi- that of the original milk sample (Fig. 2). The level of bombe- ents of either 0-60% or 0-80% acetonitrile (vol/vol)/0.01 M sin immunoreactivity in whole and skim milk was similar, trifluoroacetic acid, pH 2.3. Fractions were collected at 1- about 1.2 ng/ml in bombesin equivalents, and that in recon- min intervals at a flow rate of 1.0 ml/min; a 5-min delay was stituted dry milk was about half of this amount (Table 2). The used before initiating the gradient. To eliminate any possible total amount of immunoreactivity recovered in the acetone contamination of the equipment, blank gradients were as- extract, however, was only 17.5 ± 6.9% (n = 4). The boiling sayed by RIA as described (44). As a further precaution, the of whole milk to inhibit proteases that could interfere with injector and column were flushed with acetonitrile between the RIA (48) gave identical results. The recovery of 6.2 pmol analyses and washed daily with water, acetonitrile, metha- of bombesin added to whole milk was 90.3 ± 20.6% (n = 4).
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