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PubMed1991

The purification of tissue inhibitor of metalloproteinases-2 from its 72 kDa progelatinase complex. Demonstration of the biochemical similarities of tissue inhibitor of metalloproteinases-2 and tissue inhibitor of metalloproteinases-1.

Human gingival fibroblasts in culture were shown to secrete a 72 kDa progelatinase, of which a proportion in the medium was found to be complexed with tissue inhibitor of metalloproteinases-2 (TIMP-2). A purification procedure was devised to purify free enzyme and inhibitor. We also describe the purification of both 95 kDa progelatinase bound to TIMP-1 and free 95 kDa progelatinase from the medium of U937 cells. A polyclonal antiserum to TIMP-2 was prepared and it was shown that TIMP-1 and TIMP-2 are antigenically distinct. The ability to form stable complexes and the relative inhibitory activities of TIMP-1 and TIMP-2 towards 95 kDa and 72 kDa gelatinases, collagenase, stromelysins 1 and 2 and punctuated metalloproteinase were determined; only minor differences were found. Complex-formation between TIMP-2 and 72 kDa progelatinase was demonstrated not to reduce the metalloproteinase-inhibitory activity of TIMP-2, a finding that led to the characterization of high-molecular-mass TIMP activity. Competition experiments between progelatinases and active gelatinases for TIMPs indicated that the affinity of TIMPs for progelatinases is weaker than that for active gelatinases. In a study of the effects of TIMP-1 and TIMP-2 on progelatinase self-cleavage we found that both TIMP-1 and TIMP-2 inhibit the conversion of 95 kDa and 72 kDa progelatinases and prostromelysin into lower-molecular-mass forms. TIMP capable of complexing with progelatinase was shown to be no more efficient an inhibitor of gelatinase self-cleavage than TIMP not able to complex with progelatinase.

Amino Acid Sequence↗
PubMed2004

Synthesis and anti-HIV activity of some [Nucleoside Reverse Transcriptase Inhibitor]-C5'-linker-[Integrase Inhibitor] heterodimers as inhibitors of HIV replication.

Selected for their expected ability to inhibit HIV replication, a series of eight heterodimers containing a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and an Integrase Inhibitor (INI), bound by a linker, were designed and synthesized. For the NRTIs, d4U, d2U and d4T were chosen. For the INIs, 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (6) and 4-(3,5-dibenzyloxyphenyl)-2,4-dioxobutyric acid (9) (belonging to the beta-diketo acids class) were chosen. The conjugation of the two different inhibitors (NRTI and INI) was performed using an amino acid (glycine or beta-alanine) as a cleavable linker.

Anti-HIV Agents↗
PubMed1999

Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype.

OBJECTIVES: To study the effect of the interruption of reverse transriptase inhibitor (RTI) therapy or a switch from RTI to protease inhibitors, on the genotypic drug-resistance pattern of plasma HIV-1. METHODS: Nine patients who completely stopped all medication, and five patients who switched from a treatment with RTI to a regimen containing protease inhibitors only, were studied. Direct sequencing of the plasma HIV-1 RT and protease gene was performed on follow-up samples taken before and after the interruption of treatment. RESULTS: Comparison of the amino acid sequence of the RT and protease genes in successive samples showed the rapid reappearance of wild-type viral variants in 12 of the 14 patients studied. Wild-type virus replaced the mutant strains 14 days to 2 months after the interruption of therapy, even in patients with a long treatment history. CONCLUSION: The results of this study indicate the sustained lower fitness of mutant strains in vivo. As a result, wild-type virus remains capable of outcompeting the RT or protease mutant strains very fast after removal of the drug. These findings highlight the importance of 'treatment history' in addition to genotypic and phenotypic markers determined at one time-point, when making therapeutic decisions for patients.

Amino Acid Substitution↗
PubMed2004

Comparison of the dynamics of resistance-associated mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors after cessation of antiretroviral combination therapy.

The dynamics of mutations associated with resistance to antiretroviral drugs were analyzed after cessation of therapy. The results showed that the kinetics of the shift to wild-type amino acid residues were significantly faster for protease inhibitors, intermediate for nonnucleoside reverse transcriptase inhibitors, and slower for nucleoside reverse transcriptase inhibitors.

Anti-HIV Agents↗
PubMed1987

Interaction of the unique competitive inhibitor imidazole and related compounds with the active site metal of carbonic anhydrase: linkage between pH effects on the inhibitor binding affinity and pH effects on the visible spectra of inhibitor complexes with the cobalt-substituted enzyme.

Previous studies on the interaction of carbonic anhydrase (CA) with the unique CO2 competitive inhibitor imidazole and related compounds were all interpreted as showing that an ionizable water ligand on the metal of this zinc metalloenzyme is not displaced by inhibitor binding. Internal inconsistencies in the pH dependence of binding and the pH dependence of the visible spectra of complexes with cobalt-substituted enzyme prompted us to reinvestigate this binding. Visible spectroscopy was used to measure the binding of imidazole and 1,2,4-triazole to Co(II)-substituted human CA I and active site carboxymethylated human CA I (CmCA I) and the binding of 1,2,4-triazole to bovine CoIICA II. The limiting visible spectra for these enzyme-inhibitor adducts were also computed and examined for pH dependence. It was shown that the pKa of visible spectral changes can be independently predicted from studies on the pH dependence of binding. After consideration of possible contributions from effects of His-200 ionization in CA I and CmCA I, and His-64 in CA II, the pH effects on binding affinity and spectra were found to be of the correct magnitude to establish linkage between binding and an ionization. It was also shown, however, that pH effects on binding and spectra cannot distinguish whether neutral imidazole binds to both ionization forms of the enzyme (Zn-OH2 and Zn-OH) or whether neutral imidazole and its anion both bind to only the acid form of the enzyme, presumably after displacing the water. These findings have implications to the crystallographic interpretations on the imidazole-enzyme complex and to the catalytic mechanism of CO2 hydration.

Animals↗
PubMed2000

Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: a strategy for the design of peptidase inhibitors.

The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH(2). In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 microM) and Ala-Pro-Ala-OH (K(i) = 3 microM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 microM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 microM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.

Aminopeptidases↗
PubMed1987

Elastase inhibitors in sputum from bronchitic patients with and without alpha 1-proteinase inhibitor deficiency: partial characterization of a hitherto unquantified inhibitor of neutrophil elastase.

Anti-elastase function in sputum sol-phase from patients with alpha 1-proteinase inhibitor (alpha 1PI) deficiency was compared with sol-phase from patients with cigarette smoke-induced bronchitis and emphysema. Both alpha 1PI (2P less than 0.01) and anti-leucoprotease (ALP) (2P less than 0.01) concentrations were lower in sol-phase from the alpha 1PI-deficient group, although alpha 2-macroglobulin (alpha 2M) levels were similar. There was no difference in alpha 1PI function between the two groups, but the inhibitor was only congruent to 30% active. The absolute neutrophil elastase (NE) inhibitory capacity was similar in both groups (median 185 micrograms of NE inhibited/ml of sputum, range 80-480, for the alpha 1PI-deficient group; median 175, range 80-300, for the bronchitic group). A substantial proportion of NE inhibition in secretions could not be accounted for by the amount of alpha 1PI, ALP and alpha 2M present (median 74.8%, range 43.2-97.4, for alpha 1PI-deficient sol-phase; median 50.0%, range 0-80.8, for bronchitic sol-phase). Gel filtration of sol-phase demonstrated the presence of NE inhibition in the low molecular weight fractions which was markedly sensitive to changes in substrate concentration and ionic strength, in contrast to purified alpha 1PI and ALP. Sputum sol-phase from both groups failed to prevent hydrolysis of elastin-fluorescein or succinyltrialanyl-p-nitroanilide by NE completely during prolonged incubation in the presence of an excess of functional inhibitors. This was more apparent in secretions from subjects with alpha 1PI deficiency and may explain why such patients have a more rapidly progressive form of emphysema.

Adult↗
PubMed2002

Detection of Bowman-Birk inhibitor and anti-Bowman-Birk inhibitor antibodies in sera of humans and animals treated with Bowman-Birk inhibitor concentrate.

The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor with anticarcinogenic activities. BBI, in the form of BBI concentrate (BBIC), is currently being evaluated in clinical trials as a human cancer-preventive agent. In the present study, an enzyme-linked immunosorbent assay was used to measure BBI concentrations in serum samples collected from human subjects and animals treated with BBIC. The results demonstrate that the serum BBI concentration was higher than the baseline level for the patients after treatment with BBIC at 100-800 chymotrypsin-inhibitor units/day for 0.5, 1, 2, 4, and 6 mo. The increase in serum BBI concentration was also observed in dogs treated with BBIC at 100-1,000 mg/kg/day for 52 wk, and the increase was dose dependent. The results also indicate that anti-BBI antibodies were present in animals and the serum levels of anti-BBI antibodies increased significantly in mice treated with BBIC at 100-1,000 mg/kg/day for 15 and 26 wk. The increase in the serum level of anti-BBI antibodies in dogs treated with BBIC was not statistically significant, and no increase in the serum level of anti-BBI antibodies was observed in human subjects after BBIC treatment. These results suggest that orally ingested BBI is absorbed by human subjects and animals and that some animals develop antibodies to BBI in response to treatment with BBIC.

Animals↗
PubMed1988

Determination of leukocyte elastase-inhibitor complexes and leukocyte neutral proteinase inhibitor by enzyme immunoassays. Leukocyte elastase-inhibitor complexes in porcine blood, III.

Sensitive enzyme immunoassays for the determination of total leukocyte neutral proteinase inhibitor and polymorphonuclear elastase-leukocyte neutral proteinase inhibitor complexes are described. The usable ranges of the standard curves were from 80 ng/l to 10 micrograms/l. The relative intra-assay coefficients of variation of the tests were between 2 and 4%, and the inter-assay coefficients of variation between 4 and 10%. In vitro and in vivo studies were performed with septic pigs and isolated leukocytes. The results show that leukocyte neutral proteinase inhibitor can be used in pigs as a parameter for the development of a septicaemia.

Animals↗
PubMed2001

Effects of tetracyclines on the production of matrix metalloproteinases and plasminogen activators as well as of their natural inhibitors, tissue inhibitor of metalloproteinases-1 and plasminogen activator inhibitor-1.

OBJECTIVE: Evaluation of tetracycline effects on the expression of MMP-1, MMP-3, tissue inhibitor(s) of metalloproteinase-1 (TIMP-1), plasminogen activators (PA), and PA inhibitor-1, which are all involved in the ultimate regulation of MMP activity could provide new insight into how tetracyclines achieve their cartilage preserving effects. MATERIALS AND METHODS: We used bovine articular chondrocytes cultured in alginate gel beads for our studies which were initially treated with 10 microM tetracyclines in the presence of IL-1. Only significant effects were studied at additional concentrations. Expression of mRNA was analyzed by RT-PCR-ELISA. The activity of enzymes and TIMP was measured by functional assays; whereas, the level of PAI-1 was determined by ELISA. RESULTS: Treating chondrocytes with IL-1 induced the expression of MMPs and downregulated TIMP-1 but stimulated both the expression of PAs and PAI-1. When tested at 10 microM only minocycline reduced collagenase activity and expression of MMP-1. Further pharmacokinetic analysis revealed IC50 values of 26 microM and 16 microM for the inhibition of collagenase activity and mRNA expression, respectively. Production of MMP-3 was only decreased by tetracycline (IC50 = 45.4 microM). No effects of tetracyclines could be observed on proteoglycan degradation, TIMP activity and the production of PAs, PAI-1, and TIMP-1. CONCLUSIONS: We conclude that the inhibition of MMPs by tetracyclines occurs mainly via down-regulation of the respective gene expression.

Animals↗
PubMed1981

Evidence for exchange of inhibitors which bind to the active site of trypsin. Displacement of one inhibitor with a competitive inhibitor.

Two classes of inhibitors of trypsin (ED 3.4.21.4) have been studied, viz. active site-directed agents such as ovomucoid and active site titrants such as 4-methylumbelliferyl-4-guanidinobenzoate. The kinetics of beta-naphthyl-amidase inhibition by an active site-directed agent were markedly different from simultaneous assays of the availability of the active site towards active site titrants in the presence of the active site-directed agents. Analysis of these data indicated an exchange of active site-directed agent by subsequent addition of active site titrant. One class of trypsin inhibitor could be displaced by another from the trypsin active centre. Competitive chase experiments were designed to measure this exchange in which the active site-directed agent was first equilibrated with trypsin, then partially displaced by incremental additions of an active site titrant; the degree of active sites occupied by these two agents was then determined by active site titration with a second reagent.

Aprotinin↗
PubMed2003

Tumor tissue concentrations of the proteinase inhibitors tissue inhibitor of metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) are complementary in determining prognosis in primary breast cancer.

The purpose of this study was to investigate the association between tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and prognosis in patients with primary breast cancer and to analyze whether measurement of TIMP-1 in tumor extracts added prognostic information to that obtained from measurements of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 (PAI-1). An established sandwich enzyme-linked immunosorbent assay was thoroughly validated for the measurement of total TIMP-1 in tumor tissue extracts and used to determine levels of total TIMP-1 in 341 detergent-extracted tumor tissue samples from patients with primary breast cancer. The median age of the patients was 56 years (range, 29-75 years), and 164 were lymph node-negative, and 177 were lymph node-positive. The median follow-up time of the patients was 8.5 years (range, 7.3-11.3 years), and during follow-up 153 patients experienced recurrence of disease, and 136 patients died. In univariate survival analysis, we found a significant association between tumor tissue TIMP-1 level and both shorter recurrence-free survival (p = 0.0004) and shorter overall survival (p = 0.03). In multivariate survival analysis, higher tumor tissue TIMP-1 levels significantly and independently predicted shorter recurrence-free survival (p < 0.05, hazard ratios >1, comparing quartiles II-IV with I). In addition, we found that measurement of TIMP-1 levels added prognostic information to that obtained from measurement of PAI-1. In conclusion, high levels of TIMP-1 in tumor tissue extracts are significantly associated with a poor prognosis in patients with primary breast cancer. Furthermore TIMP-1 adds prognostic information to that obtained from PAI-1. However, further validation in independent data sets is needed.

Adult↗
PubMed2006

Calpain inhibitors and antioxidants act synergistically to prevent cell necrosis: effects of the novel dual inhibitors (cysteine protease inhibitor and antioxidant) BN 82204 and its pro-drug BN 82270.

Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 microm. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.

Animals↗
PubMed1993

Secretion of matrix metalloproteinases and their inhibitors (tissue inhibitor of metalloproteinases) by human prostate in explant cultures: reduced tissue inhibitor of metalloproteinase secretion by malignant tissues.

Unregulated secretion of matrix metalloproteinases (MMPs) or their endogenous protein inhibitors (tissue inhibitor of metalloproteinases, TIMPs) has been implicated in tumor invasion and metastasis. Species of MMPs and TIMPs secreted by epithelial cultures of normal, benign, and malignant prostate were identified and their levels were compared. Fragments of fresh tissue were cultured in a serum-free medium that supported the outgrowth of prostatic epithelial cells. Biochemical analysis of the conditioned media by gelatin zymography and enzyme assays showed that both normal and neoplastic tissues secreted latent and active forms of both M(r) 72,000 type IV collagenase (MMP-2) and M(r) 92,000 gelatinase (MMP-9). However, conditioned media from malignant prostate explants contained a higher proportion of the active form of MMP-2. Significant amounts of free TIMPs were secreted by normal juvenile and adult prostates, but they were either markedly reduced or not detectable in conditioned media from neoplastic tissues. These findings suggest that there is an imbalance of secretion between MMPs and TIMPs in prostatic carcinoma.

Adult↗
PubMed2001

[Cyclooxygenase (COX)-2 selective inhibitors: aspirin, a dual COX-1/COX-2 inhibitor, to COX-2 selective inhibitors].

Aspirin was developed as a non-steroidal anti-inflammatory drug (NSAID) in 1899. During the century after that, aspirin has been found to show its anti-inflammatory, analgesic and anti-pyretic activities by reducing prostaglandins biosynthesis through inhibition of cyclooxygenase (COX); and then COX was found to be constituted of two isoforms, constitutive COX-1 and inducible COX-2. Currently, novel NSAIDs, acting through selective inhibition of COX-2, that have efficacy as excellent as aspirin with significantly lower incidence of gastrointestinal adverse effects are available in America and some other countries, but not in Japan. Physiological and pathophysiological roles of COX-1 and COX-2 have been explained from studies in experimental animals, but there are many differences in species and diseases between animals and humans. Thus, physiological and pathophysiological roles of COX-2 were considered from the standpoint of clinical effects of the two latest COX-2 selective inhibitors, celecoxib and rofecoxib, on inflammation, pain, fever and colorectal cancer together with their adverse effects on gastrointestinal, renal and platelet functions; and the usefulness and limits of COX-2-selective inhibitors were discussed with the trends of new NSAIDs development.

Animals↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed1976

Isolation and characterization of alpha2-plasmin inhibitor from human plasma. A novel proteinase inhibitor which inhibits activator-induced clot lysis.

A procedure is presented for purifying a novel proteinase inhibitor in human plasma whose apparent unique biological property is to inhibit efficiently the lysis of fibrin clots induced by plasminogen activator. The final product is homogeneous as judged by disc gel electrophoresis, and immunoelectrophoresis. Its molecular weight estimated by sodium dodecyl sulfate gel electrophoresis or sedimentation equilibrium is 67,000 and 63,000, respectively. The inhibitor is a glycoprotein consisting polypeptide chain containing 11.7% carbohyrate. It migrates in the alpha2-globulin region in immunoelectrophoresis. The inhibitor is chemically and immunologically different from all the other known inhibitors in plasma. Inhibition of plasmin by the inhibitor is almost instantaneous even at 0 degrees, in contrast to the slow inhibition of urokinase (plasminogen activator in urine). Plasminogen activation by urokinase-induced clot lysis is inhibited by the inhibitor mainly through a mechanism of instantaneous inhibition of plasmin formed and not through the inhibition of urokinase. The inhibitor also inhibits trypsin. Consequently, it is suggested that this newly identified inhibitor is named alpha2-plasmin inhibitor or alpha2-proteinase inhibitor. A specific antibody directed against the inhibitor neutralizes virtually all inhibitory activity of plasma to activator-induced clot lysis. Immunochemical quantitation of the inhibitor was specific antiserum to the inhibitor and the purified inhibitor as a standard indicates that the concentration of the inhibitory in the serum of a healthy man is in or near the range of 5 to 7 mg/100 ml, which is the lowest concentration among the concentration of the proteinase inhibitors in plasma. The inhibitor and plasmin, trypsin, or urokinase form a complex which cannot be dissociated with denaturing and reducing agents. The formation of the enzyme-inhibitor complex occurs on a 1:1 molar basis and is associated with the cleavage of a unique peptide bone, which is most clearly demonstrated in the interaction of the inhibitor and beta-trypsin. In the complex formation between the inhibitor and plasmin, the inhibitor is cross-linked with the light chain which contains the active site of plasmin. It is suggested that, in a fashion analogous to complex formation between alpha1-antitrypsin and trypsin, the cross-links are formed between the active site serine of the enzyme and the newly formed COOH-terminal residue of the inhibitor, with cleavage of a peptide bond.

Amino Acids↗
PubMed1986

In vivo metabolism of inter-alpha-trypsin inhibitor and its proteinase complexes: evidence for proteinase transfer to alpha 2-macroglobulin and alpha 1-proteinase inhibitor.

Inter-alpha-trypsin inhibitor was purified by a modification of published procedures which involved fewer steps and resulted in higher yields. The preparation was used to study the clearance of the inhibitor and its complex with trypsin from the plasma of mice and to examine degradation of the inhibitor in vivo. Unlike other plasma proteinase inhibitor-proteinase complexes, inter-alpha-trypsin inhibitor reacted with trypsin did not clear faster than the unreacted inhibitor. Studies using 125I-trypsin provided evidence for the dissociation of complexes of proteinase and inter-alpha-trypsin inhibitor in vivo, followed by rapid removal of proteinase by other plasma proteinase inhibitors, particularly alpha 2-macroglobulin and alpha 1-proteinase inhibitor. Studies in vitro also demonstrated the transfer of trypsin from inter-alpha-trypsin inhibitor to alpha 2-macroglobulin and alpha 1-proteinase inhibitor but at a much slower rate. The clearance of unreacted 125I-inter-alpha-trypsin inhibitor was characterized by a half-life ranging from 30 min to more than 1 h. Murine and human inhibitors exhibited identical behavior. Multiphasic clearance of the inhibitor was not due to degradation, aggregation, or carbohydrate heterogeneity, as shown by competition studies with asialoorosomucoid and macroalbumin, but was probably a result of extravascular distribution or endothelial binding. 125I-inter-alpha-trypsin inhibitor cleared primarily in the liver. Analysis of liver and kidney tissue by gel filtration chromatography and sodium dodecyl sulfate gel electrophoresis showed internalization and limited degradation of 125I-inter-alpha-trypsin inhibitor in these tissues. No evidence for the production of smaller proteinase inhibitors from 125I-inter-alpha-trypsin inhibitor injected intravenously or intraperitoneally was detected, even in casein-induced peritoneal inflammation. No species of molecular weight similar to that of urinary proteinase inhibitors, 19,000-70,000, appeared in plasma, liver, kidney, or urine following injection of inter-alpha-trypsin inhibitor.

Alpha-Globulins↗