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PubMed1980

Biosynthesis of leupeptin. IV. Is protein turnover in leupeptin producer cells affected by leupeptin?

There was no significant difference between the rates of protein degradation in cells of a leupeptin-producing strain and that of a leupeptin-nonproducing strain, the latter being derived from the former by mutation. Protein autodigestion in a cell homogenate of the leupeptin producer was sensitive to EDTA and chymotrypsin and less sensitive to leupeptin. On the contrary, protein degradation caused by exogenous trypsin in a similar homogenate was highly sensitive to leupeptin. A labeling experiment with [14C]-arginine of a culture of the leupeptin producer strain revealed that leupeptin was accumulated mostly in the medium and only slightly in the cells; the ratio between the amount in the medium and that in the cells was about 250:1. In contrast, leupeptin acid, the proximal intermediate having no antiplasmin activity, showed a ratio of 5:1.

Bacterial Proteins↗
PubMed1981

Purification and properties of an enzyme reducing leupeptin acid to leupeptin.

An enzyme catalyzing the reduction of leupeptin acid to leupeptin was partially purified from a cell extract of Streptomyces roseus MA839-A1, a leupeptin producer. The enzyme was tentatively named leupeptin acid reductase. The molecular weight was estimated to be 320,000 by chromatography on Sepharose 6B. The reductase eluted with leupeptin acid synthetase both in molecular sieve chromatography and in affinity chromatography. The main properties of the reductase were: (1) ATP and NADPH were required for activity. ATP could not be replaced by GTP, ADP or AMP. NADPH could not be replaced by NADH. (2) Michaelis constants for ATP and NaDPH were 4.2 . 10(-5) M and 1.3 10(-6) M, respectively. (3) The enzyme was inhibited by leupeptin, the reaction product, and antipain. Both inhibitors have an L-argininal residue at the C-terminal structure. (4) The enzyme did not catalyze the conversion of leupeptin to leupeptin acid. Leupeptin acid reductase and leupeptin acid synthetase were found in the 10,000 x g pellet of the cell homogenate. The reductase was not released as readily from the pellet as the synthetase either by washing or by repeated freeze-thawing. Synthesis of leupeptin from acetyl-CoA, L-lucine and L-arginine in vitro was accomplished by combining leucine acyltransferase and the enzyme complex consisting of leupeptin acid synthetase an leupeptin acid reductase.

Adenosine Triphosphate↗
PubMed1998

Characterization of the leupeptin-inactivating enzyme from Streptomyces exfoliatus SMF13 which produces leupeptin.

Leupeptin-inactivating enzyme (LIE) was purified from Streptomyces exfoliatus SMF13 by ammonium sulphate fractionation of cell-free culture broth, ultrafiltration, anion-exchange chromatography on DEAE-Sephadex A-50 and gel filtration chromatography on Sephadex G-75. The molecular mass of the purified enzyme was measured as 34700 Da and the N-terminal amino acid sequence was APTPPDIPLANVPA. Acetyl-leucine, leucine and argininal were identified as the products of leupeptin inactivated by the LIE, indicating that leupeptin is inactivated by hydrolysis of peptide bond between leucine and leucine and between leucine and argininal of leupeptin (acetyl-leucine-leucine-argininal). Synthetic-peptide substrates specificity of LIE showed that LIE has absolute specificity for peptide bonds with leucine in the P1 position, suggesting that LIE is a leucine-specific protease. The optimum pH and temperature were pH 9.0 and 45 degrees C, respectively. LIE activity was inhibited by metalloprotease inhibitors such as EDTA, EGTA, o-phenanthroline and bestatin, but activated by Mg2+ and Ca2+, suggesting that the enzyme is a metalloprotease. Aerial-mycelium growth and aerial spore formation of S. exfoliatus SMF13 were inhibited by the addition of bestatin, an inhibitor of LIE. The inhibition of morphological differentiation was due to the inhibition of trypsin-like protease (TLP) activity, which is essential for aerial-mycelium formation and is inhibited specifically by remaining leupeptin that was not inactivated. These results show that LIEs play a role in controlling the amount of leupeptin during colony development. Therefore, it is suggested that the physiological function of LIE is to inactivate leupeptin when or where TLP activity is required for aerial-mycelium formation.

Amino Acid Sequence↗
PubMed1989

Active and inactive forms of the transition-state analog protease inhibitor leupeptin: explanation of the observed slow binding of leupeptin to cathepsin B and papain.

Leupeptin and similar peptide argininal (arginine aldehyde) transition-state analog protease inhibitors exist in three covalent forms in aqueous solution, the leupeptin hydrate (IH), a cyclic carbinolamine form (IC) generated by the addition of the guanidino epsilon N to the aldehydic carbon, and the free aldehyde form (IA). 1H NMR in D2O show their equilibrium concentrations to be 42, 56, and 2% for IH, IC (R and S enantiomers), and IA. The rates of conversion of (formula; see text) were determined by 1H NMR in D2O by trapping IA with semicarbazide. Application of a deuterium isotope effect of 2.8 led to rate constants in H2O for kC of 0.092 min-1 and kD of 0.73 min-1. The equilibrium concentration of IA and rates for kC and kD are then used to explain the lag phase in the inhibition of cathepsin B and papain by leupeptin. Two circumstances are observed. (i) At micromolar concentrations of leupeptin and papain the binding of leupeptin is biphasic with rate constants identical to kD and kC. (ii) At more dilute nanomolar concentrations of total leupeptin and proteases, the observed lag phase for approach to steady-state inhibition (with rate constant k') is now explained by the low values of the koff rate constants (0.072 min-1 for cathepsin B and 0.024 min-1 for papain) together with the extremely low concentrations of the active inhibitor form IA, with k' = kon[IA] + koff. While kon[IA] is slow, the second-order rate constant kon is found to be quite fast, 1.2 x 10(7) M-1 s-1 for cathepsin B and 1.8 x 10(7) M-1 s-1 for papain. Thus, the binding of leupeptin to cathepsin B and papain may show a lag phase, but this is not due to slow binding.

Algorithms↗
PubMed1986

Assay of plasma leupeptin using the reversible binding of leupeptin to bovine pancreatic trypsin.

A competitive binding radioassay for leupeptin has been developed utilizing the reversible binding of leupeptin to bovine pancreatic trypsin. An ethanol precipitation step was introduced to separate trypsin-bound leupeptin from its free form. Advantages of this method are simplicity of the procedure and avoidance of the preparation of antiserum. The possible metabolites of leupeptin exhibit no significant inhibitory effect on leupeptin-trypsin binding in this system. This method was applied to the determination of plasma leupeptin levels in dogs after oral administration of the peptide.

Animals↗
PubMed1987

Mode of action of bestatin and leupeptin to induce the accumulation of acid soluble peptides in rat liver in vivo and the properties of the accumulated peptides. The important role of bestatin- and leupeptin-sensitive proteases in the protein degradation pathway in vivo.

The chemical properties of acid soluble peptides accumulated in liver or excreted into urine after administration of bestatin or leupeptin to rats were investigated extensively. At the same time, the effects of glucagon on the bestatin-induced accumulation of acid soluble peptides were studied. The results show the important role of bestatin- and leupeptin-sensitive proteases in the degradation pathway of intracellular proteins in vivo.

Aminopeptidases↗
PubMed1979

Biosynthesis of leupeptin. II Purification and properties of leupeptin acid synthetase.

An enzyme which condenses acetyl-L-leucyl-L-leucine and L-arginine into acetyl-L-leucyl-L-leucyl-L-leucyl-L-arginine (leupeptin acid) was partially purified from a cell extract of Streptomyces roseus MA839-A1. With respect to this catalytic activity, the enzyme showed the following characteristics: ATP is essential; optimum pH is 9.5; the activity is inhibited either by EDTA or pyrophosphate or N-ethylmaleimide. The molecular weight of the enzyme is about 260,000 daltons. It also catalyzes some other extension reactions, such as, acetyl-L-leucine+L-leucine+L-arginine leads to leupeptin acid, and acetyl-L-leucine+L-leucine leads to acetyl-L-leucyl-L-leucine, but neither L-leucine+L-arginine leads to (L-leucyl)1--2-L-argining, nor acetyl-L-leucine+L-arginine leads to acetyl-L-leucyl-L-arginine. ATP-PPi exchange, catalyzed by this enzyme, proceeds with either acetyl-L-leucine, or acetyl-L-leucyl-L-leucine or L-leucine, but not with acetate or arginine.

Adenosine Triphosphate↗
PubMed1984

Effect of leupeptin on the autophagic vacuolar system of rat hepatocytes. Correlation between ultrastructure and degradation of membrane and cytosolic proteins.

Injection of leupeptin (an inhibitor of lysosomal cathepsins B, H, and L) to nonstarved rats causes an expansion of the autophagic vacuolar (AV) system in hepatocytes. Readily identifiable cytoplasmic constituents were seen within the AVs shortly after the administration. Later, the contents of the AVs seemed to reach more advanced stages of degradation. Liver AVs were purified by a one-step centrifugation of a crude mitochondrial lysosomal fraction in a discontinuous metrizamide gradient after exposing the rats to leupeptin for varying periods of time. Leupeptin caused alterations of the AV fraction that were time dependent. Initially, i.e., after 30 minutes of leupeptin exposure, mature (secondary) lysosomes clearly dominated over nascent AVs. The situation was reversed when fractionation was performed 1 or 2 hours following the injection of leupeptin. Now, the AVs were more frequent than the mature lysosomes. Later, the proportion of mature lysosomes was again larger. An increase in dense bodies was noted after 16 hours of leupeptin treatment. The proteolytic capacity of the AVs at different stages of maturation was measured after labeling liver proteins with an injection of L-1-14C-leucine 16 hours before sacrifice. AVs were purified after varying times of exposure to leupeptin. The proteolysis decreased greatly 1 to 2 hours following the injection of leupeptin but never ceased. On the other hand, lipolysis seemed unaffected by leupeptin using a similar experimental protocol as for proteolysis. If the animals were subjected to more lasting exposure to leupeptin before fractionation, proteolysis increased, displaying a peak higher than control, occurring after approximately 4 hours. The degradation gradually returned to control values after 16 hours. A catch-up in proteolysis was thus observed. The time course of proteolysis was reflected in the protein content in the AV fraction. After an initial increase that coincided with the lowered proteolysis, it returned to control level. Marker enzyme activities for endoplasmic reticulum and mitochondria (G6Pase and succinate-cytochrome c reductase) followed the same pattern. The AV content of the cytosolic enzymes lactate dehydrogenase and aldolase reached as high as 2.30 and 2.80% of the values in the homogenate during the 1st hour of leupeptin exposure. From these data the half-lives of the enzymes were calculated. They were: for aldolase, 43 hours; for LDH, 68 hours. This suggests that AVs account for a substantial proportion of degradation not only of organelles but also of soluble cytosolic enzymes.

Animals↗
PubMed2004

Inhibition of calpains, by treatment with leupeptin, improves motoneuron survival and muscle function in models of motoneuron degeneration.

The effect of treatment with leupeptin, a calpain inhibitor, on motoneuron survival and muscle function was examined in in vitro and in vivo models of motoneuron degeneration. Exposure of primary rat motoneurons to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) is an established in vitro model of excitotoxic motoneuron death. Here we show that leupeptin treatment improved motoneuron survival following exposure to AMPA (50 microM). Application of leupeptin (100 microM) to AMPA treated cultures rescued many motoneurons so that 74% (+/-3.4 S.E.M., n=5) survived compared with only 49% (+/-2.4 S.E.M., n=5) in untreated cultures. The effect of treatment with leupeptin on motoneuron survival and muscle function was also examined in vivo. In 3 day-old rats, the sciatic nerve was crushed and at the time of injury, a silicon implant containing leupeptin was inserted onto the lumbar spinal cord. The effect on long-term motoneuron survival and muscle function was assessed 12 weeks after injury. The results showed that there was long-term improvement in motoneuron survival in the leupeptin treated group. Thus, in untreated animals 12 weeks after nerve crush only 30% (+/-2.8. S.E.M., n=3) of sciatic motoneurons survived compared with 43% (+/-1.5 S.E.M., n=3) in the leupeptin-treated group. This improvement in motoneuron survival was reflected in a significant improvement in muscle function in the leupeptin-treated group. For example in the soleus muscle of treated rats 20.8 (+/-1.40 S.E.M., n=5) motor units survived compared with only 14.6 (+/-1.21 S.E.M., n=5) in untreated animals. Thus, treatment with leupeptin, a calpain inhibitor, rescues motoneurons from cell death and improves muscle function following nerve injury.

Animals↗
PubMed1995

Physiological roles of leupeptin and extracellular proteases in mycelium development of Streptomyces exfoliatus SMF13.

Streptomyces exfoliatus SMF13 produced leupeptin, chymotrypsin-like protease (CTP), metalloprotease, and trypsin-like protease (TLP) extracellularly. The activity of TLP was specifically inhibited by leupeptin. Production of leupeptin was closely associated with growth but leupeptin was inactivated by leupeptin-inactivating protein (LIP) when growth reached the stationary phase in submerged cultures, or when aerial mycelia started to form on surface cultures. Autolysis of mycelia after the stationary phase in submerged cultures was apparently retarded by the addition of leupeptin; on surface cultures, aerial mycelium formation was clearly retarded by the addition of leupeptin. We propose that CTP participates primarily in utilization of a proteinaceous nitrogen source, that TLP functions as an essential enzyme involved in the metabolism of mycelial protein, that leupeptin inhibits the activity of TLP and that LIP inactivates leupeptin. The cascade of regulatory actions of the compounds, which are produced sequentially during mycelium development, may provide selective advantages in adverse culture conditions.

Amino Acid Sequence↗
PubMed1988

Inhibition of thrombin-induced platelet activation by leupeptin. Implications for the participation of calpain in the initiation of platelet activation.

Inhibitors of calcium-dependent proteases (calpains) such as leupeptin and antipain have been shown to selectively inhibit platelet activation by thrombin. Based upon this observation, it has been proposed that calpains play a role in the initiation of platelet activation. In the present studies, we have examined the effect of leupeptin on the earliest known event in thrombin-induced platelet activation: the interaction between the agonist, its receptors, and the guanine nucleotide-binding proteins which stimulate phospholipase C (Gp) and inhibit adenylyl cyclase (Gi). We found that leupeptin inhibited thrombin's ability to stimulate phosphoinositide hydrolysis, suppress cAMP formation, and dissociate Gp and Gi into subunits. Leupeptin had no effect, however, on the same responses to other agonists or on thrombin binding to platelets. Although these observations might suggest, as others have concluded, that calpain is involved in the initiation of platelet activation by thrombin, we also found that: 1) substituting platelet membranes for intact platelets and decreasing the free Ca2+ concentration below the threshold required for calpain activation did not diminish the effects of leupeptin on phosphoinositide hydrolysis and cAMP formation, 2) washing the platelets after incubation with leupeptin reversed the effects of the inhibitor, 3) permeabilizing the platelets with saponin did not enhance the inhibitory effects of leupeptin, and 4) leupeptin inhibited the proteolysis of fibrinogen and the hydrolysis of S2238 by thrombin. Similar results in these assays were obtained with antipain. Therefore, our observations suggest that the inhibition of platelet activation by leupeptin is due to a direct interaction with thrombin and need not reflect a role for calpain in the initiation of platelet activation.

Adenosine Diphosphate Ribose↗
PubMed1984

Effects of the protease inhibitor leupeptin on proteolytic activities and regeneration of mouse skeletal muscles after exercise injuries.

Leupeptin, a nontoxic thiol protease inhibitor, has been proposed to have therapeutic use in hereditary muscular dystrophies. The purpose of this study was to characterize the in vivo changes in proteolytic activity of skeletal muscles induced by the repeated administration of leupeptin. Further, whether the modulation of proteolytic capacity by leupeptin affects the repair process of muscle injuries caused by heavy exercise was studied. Leupeptin was administered in mice intraperitoneally at a dose level of 15.5 mg/kg twice a day for 9 days. Leupeptin, known to be an inhibitor of cathepsin B both in vitro and after a single injection in vivo, paradoxically induced an increase of cathepsin B activity in mouse skeletal muscles after repeated administration. In addition, leupeptin administration for 9 days increased the activities of cathepsins C and D, as well as the rate of acid autolysis. The activity of beta-glucuronidase also increased, while those of arylsulfatase, ribonuclease, and alkaline protease were unaffected. No histopathologic changes were observed. At the low dosage used, leupeptin had no effect on the repair process of skeletal muscle after exercise injuries, although several proteolytic processes occur during the regeneration. It is suggested that the increase of acid protease activities in skeletal muscles is an adaptive response to the administration of the proteolytic inhibitor leupeptin and that leupeptin can be administered without prevention or delay of regenerative processes after the onset of myopathic changes.

Animals↗
PubMed1981

Proteolytic modification of rat liver fructose-1,6-bisphosphate aldolase by administration of leupeptin in vivo.

When leupeptin, a thiol protease inhibitor of microbial origin, was injected into rats, the activity of fructose-1,6-bisphosphate aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) in the liver decreased to about 60% of that in control rats. However, the concentration of aldolase protein in the liver extracts, measured with a specific antibody obtained with enzyme purified on a phosphocellulose column, remained unchanged. Injection of leupeptin also caused a marked increase in the activities of free lysosomal proteases, such as cathepsin B (EC 3.4.22.1), cathepsin L (EC 3.4.22.-), cathepsin D (EC 3.4.23.5) and lysosomal carboxypeptidase A in the cytosol fraction. A clear inverse relationship between aldolase and cathepsin B activities in the cytosol fraction was demonstrated. The possibility that the less active form of aldolase detected in the livers of leupeptin-treated rats was produced during homogenization was excluded by showing that the aldolase activity was not changed by addition of various protease inhibitors to the homogenization medium., When insulin was coinjected with leupeptin, increase in the activity of free cathepsin L and decrease of activity of aldolase produced by the injection of leupeptin was prevented. These findings indicate that modification of aldolase may be due to the action of a lysosomal protease(s). Enhanced sensitivity of lysosomes to osmotic shock was demonstrated in the livers of leupeptin-treated rats, suggesting that the lysosomal membrane is labilized by administration of leupeptin. Incubation of the purified aldolase with the lysosomal fraction produced the same changes in properties of aldolase as those observed in vivo on injection of leupeptin.

Animals↗
PubMed1987

Treatment of experimental autoimmune myasthenia gravis in rabbits with leupeptin, a protease inhibitor.

We injected 12 New Zealand white rabbits intraperitoneally with 15 mg/kg Leupeptin on alternative days for about 4 months. After 1 week of Leupeptin treatment, they were challenged with purified acetylcholine receptor (AChR) from Torpedo californica in Freund's complete adjuvant. All control animals died within 60 days. Six animals treated with Leupeptin did not develop EAMG in spite of repeated AChR injections. Three animals developed clinical signs of EAMG after 65 days. The clinical course was short in the one that survived and prolonged in the 2 that finally died. All animals (Leupeptin-treated and controls) had circulating anti-AChR antibodies. Among the survivors, titers were slightly lower and EMG repetitive stimulation tests were normal. Leupeptin (0.02-200 mM) did not prevent curaremimetic [3H]toxin binding to AChR in membranes or in solution, nor dissociate AChR-toxin-antibody complexes. Immune response to antigens other than receptor remained intact in Leupeptin-treated animals. Leupeptin was not toxic at the doses given. The mechanism of this protection is not well understood. Leupeptin seems to decelerate the turnover rate of AChR induced by anti-AChR antibodies and/or to decrease the complement-mediated immune attack against the muscle end-plate.

Animals↗
PubMed1982

Appearance of autolysosomes in rat liver after leupeptin treatment.

The administration to rats of leupeptin produced prominent numbers of enlarged and irregularly shaped autolysosomes in hepatocytes. Percoll density equilibration of crude lysosomal fractions from rat livers showed that most lysosomal enzyme migrated form normal lysosomal density fractions toward higher density fractions within 30 min after leupeptin injection. The denser particles were ultrastructurally identified with the autolysosomes. In analysis by differential centrifugation of the liver homogenates, lysosomal enzymes became sedimentable with particles of greater sedimentation rate within 30 min after leupeptin injection. These changes in physical properties of lysosomes reverted to normal after 24 h, and concomitant disappearance of autolysosomes in hepatocytes was observed by electron microscopy. When the time course of distribution of leupeptin in subcellular fractions was analyzed, particle-bound leupeptin shifted with time to larger particle fractions in parallel with the shift of lysosomal enzyme distribution. Upon injection with leupeptin, cathepsin B activity was inhibited by more than 80% for about 3 h and was gradually restored to a normal level after 24 h. Leupeptin treatment caused marked delay of the degradation of endocytosed FITC-labeled asialofetuin in hepatic lysosomes, and its inhibitory effect lasted for over 9 h after the injection. It was suggested that autophagy is probably a normal process of protein degradation in hepatocytes, and because of a retarded digestion of sequestered materials, autolysosomes persisted for a long period and made up the majority of the lysosome population in the leupeptin-treated cells.

Acid Phosphatase↗
PubMed1983

Inhibition of proteolysis in rat yolk sac as a cause of teratogenesis. Effects of leupeptin in vitro and in vivo.

Conceptuses from 9.5-day pregnant rats were cultured for 48 h in heat-inactivated homologous serum to which leupeptin, a specific inhibitor of the lysosomal cysteine-proteinases, was added for the final or the penultimate 6 h. The presence of leupeptin (25 micrograms/ml or above) increased the protein content of yolk sacs at harvesting to approximately twice the control value. The protein content of the embryo at harvesting was lower than that of controls. When 125I-labelled polyvinylpyrrolidone was added to the culture serum for the final 6 h of culture, radioactivity was found in the yolk sac at harvesting, but not in the embryo. The presence of leupeptin did not affect the rate of uptake of the radiolabelled macromolecule by the yolk sac, nor facilitate its entry into the embryo. When formaldehyde-denatured 125I-labelled bovine serum albumin was added to the culture medium for the final 6 h of culture, little radioactivity was found in the yolk sac at harvesting, and barely any was found in the embryo. Trichloroacetic acid-soluble radioactivity was found in the culture serum. The presence of leupeptin sharply increased the levels of radioactivity in the yolk sac (but not the embryo) and sharply decreased the acid-soluble radioactivity of the culture medium. When rat serum whose proteins were labelled with [3H]leucine was used as culture medium, radioactivity was found in both yolk sac and embryo at harvesting. The presence of leupeptin increased the amount found in the yolk sac and decreased that found in the embryo. These results are interpreted as follows. Leupeptin enters the lysosomes of the yolk sac, inhibiting their cysteine proteinases. The digestion of proteins pinocytosed by the yolk sac is consequently inhibited, resulting in the accumulation of protein by the yolk sac and a decreased flow of amino acids to the embryo. Leupeptin (50 mg/kg), injected into pregnant rats at either 8.5 days or 9.5 days of gestation, induced congenital malformation in the offspring. It is proposed that leupeptin exerts its teratogenic action by inhibiting proteolysis in the lysosomes of the yolk sac, and so depriving the developing embryo of its supply of amino acids at a critical stage of development.

Abnormalities, Drug-Induced↗
PubMed1985

Leupeptin as a tool for the detection of the sites of catabolism of rat high-density lipoprotein apolipoproteins A-I and E.

Leupeptin, an inhibitor of lysosomal cathepsin activity, was injected intravenously into male rats. Tissues obtained from leupeptin-treated animals showed a depressed cathepsin activity when compared with tissues from saline-treated control animals. Leupeptin treatment did not change the hepatic activities and subcellular distribution of marker enzymes for mitochondria, microsomes and plasma membranes. Hepatic lysosomal cathepsin activity was specifically inhibited, but the subcellular distribution of all lysosomal marker enzymes tested was changed, indicating the occurrence of enlarged lysosomes in the leupeptin-treated animals. No significant differences were observed in the serum concentrations of protein, cholesterol, cholesteryl esters, phospholipids and apolipoproteins A-I, A-IV and E between leupeptin-treated rats and control animals. When radioiodinated asialofetuin was injected intravenously, the radiolabel was retained for an extended period of time in the liver of leupeptin-treated animals, indicating diminished catabolism of this protein in the liver. When rat high-density lipoprotein, labelled specifically in the apolipoprotein A-I or E moiety was injected intravenously, only the kidneys and the liver showed a leupeptin-induced accumulation of radioactivity. These studies provide evidence for an important contribution of the kidneys and the liver to the in vivo catabolism of high-density lipoprotein apolipoproteins, using a method completely different from sugar-containing labelling compounds.

Animals↗
PubMed1987

Leupeptin inhibits the transformation of glucocorticoid receptor.

The effect of leupeptin upon the transformation of the glucocorticoid receptor was tested. When the labeled receptor was treated with heat or high salt in the presence of leupeptin, the binding to DNA-cellulose decreased in a dose-dependent manner. We observed 50% inhibition with about 40 mM leupeptin. The addition of leupeptin after the transformation procedures did not inhibit the binding to DNA-cellulose. In gradient centrifugation, 40 mM leupeptin retained approximately 10S, untransformed form. Elution profiles from DEAE-cellulose showed the preservation of the peak eluted with 0.2 M KCl, corresponding to the untransformed form. These results indicate that leupeptin might have the similar effects to molybdate in regard to blocking the transformation of rat liver glucocorticoid receptor, though the effects with leupeptin were not as great as those seen with molybdate.

Adrenalectomy↗