Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In alcoholic liver disease, it is well-known that ethanol and its metabolites induce hepatic fibrosis. With progress in injury, the accumulation of extracellular matrix, which consists of type I, III, IV collagen and laminine, occurs in the area of hepatic central vein and perihepatocytes. In these fibrotic areas, the activated lipocytes (transitional cell and myofibroblast, etc), which may be transformed from Ito cell by fibrogenic cytokines, are increased and may play an important role in the progression of alcoholic hepatic fibrosis. Actually, a recent study indicates that chronic ethanol consumption sensitizes the response of lipocytes to TGF beta. It is observed that acetaldehyde and lactate stimulate collagen production and that acetaldehyde increases collagen mRNA expression and collagen gene transcription in cultured human fibroblast. The extracellular matrix is degraded by matrix metalloproteinases (MMPs). The collagenase activity is decreased in progression of liver cirrhosis and is regulated by fibrogenic cytokines. Acetaldehyde decreases by 50% of the collagenase mRNA expression in fibroblast. It is clear that hepatic fibrosis may progress under the balance of collagen production and degradation, which are associated with fibrogenic cytokines. Thus, in the search for mechanism of alcoholic hepatic fibrosis, it is important to elucidate how ethanol and its metabolites influence the activation of lipocytes through fibrogenic cytokines.
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PMID:[Alcoholic liver cirrhosis]. 811 91

This study was designed to investigate whether the changes in lysine hydroxylation known to occur in hypertrophic tendon occur randomly or at specific lysine residues in the type I collagen molecule. Peptides corresponding to the two known major cross-linking sites of type I collagen (a lysine (or hydroxylysine) at position 9N cross-linked to a hydroxylysine at 930 and a lysine (or hydroxylysine) at position 16C cross-linked to a hydroxylysine at position 87) were prepared by collagenase digestion, size fractionation, and separation by high performance liquid chromatography from normal chicken tendon and from chicken tendon subjected to increased tensile load as a result of muscle hypertrophy. The ratio of the difunctional cross-links dihydroxylysinonorleucine to hydroxylysinonorleucine in normal tendon is 0.75:1; this ratio is increased to 6:1 in hypertrophic tendon. The dihydroxylysinonorleucine to hydroxylysinonorleucine ratio is increased to the same extent in samples of the purified cross-linked peptides derived from both the N-terminal and C-terminal lysine aldehyde residues. On the other hand, the relative hydroxylysine content of preparations of the pooled larger helical peptides obtained by cyanogen bromide digestion of normal and hypertrophic tendons was essentially identical. These results demonstrate that there is a specific increase in hydroxylation of only the N- and C-terminal non-helical lysine residues that participate in the formation of the reducible difunctional cross-links of type I collagen in hypertrophic tendon, while the extent of hydroxylation of lysine residues in the helical regions is not affected. The specific mechanism by which the enzyme lysyl hydroxylase acting on its substrate can distinguish between lysine residues destined to be in non-helical versus helical regions in a nascent collagenous peptide that has not yet attained its final secondary structure remains to be defined.
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PMID:Tendon hypertrophy is associated with increased hydroxylation of nonhelical lysine residues at two specific cross-linking sites in type I collagen. 824 92

Three decades of research in ethanol metabolism have established that alcohol is hepatotoxic not only because of secondary malnutrition, but also through metabolic disturbances associated with the oxidation of ethanol. Some of these alterations are due to redox changes produced by the NADH generated via the liver ADH pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Exaggeration of the redox change by the relative hypoxia, which prevails physiologically in the perivenular zone, contributes to the exacerbation of the ethanol-induced lesions in zone III. Gastric ADH also explains first-pass metabolism by ethanol; its activity is low in alcoholics and in females and is decreased by some H2 blockers. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last 20 years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450 (P4502E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by P4502E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion, but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes GSH depletion, free-radical-mediated toxicity, and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis; both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and lipocytes); ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding may eventually improve therapy with drugs and nutrients. Encouraging results have been obtained with some "super" nutrients. On the one hand, SAMe, the active form of methionine, was found to attenuate the ethanol-induced depletion in SAMe and GSH and associated mitochondrial lesions. On the other hand, phosphatidylcholine, purified from polyunsaturated lecithin, was discovered to oppose the ethanol-induced fibrosis by decreasing the activation of lipocytes to transitional cells, and possibly also by stimulating collagenase activity, an effect for which dilinoleoylphosphatidylcholine, its major phospholipid species, was found to be responsible.
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PMID:Biochemical factors in alcoholic liver disease. 833 2

Increased acetaldehyde levels have been found in non-alcoholic liver diseases and an acetaldehyde-collagen adduct has been reported in rats with CCl4-induced cirrhosis. In cytosol and microsomes of rats with cirrhosis produced by N-nitrosodimethylamine, a similar acetaldehyde-protein adduct of approximately 200 kD was recognized by rabbit IgG raised against either an in vitro produced hemocyanin-acetaldehyde adduct or an in vivo occurring P4502E1-acetaldehyde adduct isolated from alcohol-fed rats, as well as by anti-rat collagen (I) IgG. Its immune complexes contained 3 proteins that reacted with the anti-collagen IgG and were digested by collagenase: 2 proteins with molecular weights similar to procollagens alpha 1 and alpha 2, and a beta 1,2(I)-like protein which was readily produced by in vitro modification of cytosol with acetaldehyde.
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PMID:Acetaldehyde-collagen adducts in N-nitrosodimethylamine-induced liver cirrhosis in rats. 846 25

Alcohol affects the liver through metabolic disturbances associated with its oxidation. Redox changes produced by the hepatic alcohol dehydrogenase pathway affect lipid, carbohydrate and protein metabolism. Ethanol is also oxidized in liver microsomes by the ethanol-inducible cytochrome P4502E1, resulting in ethanol tolerance and selective hepatic perivenular damage. Furthermore, P4502E1 activates various xenobiotics, explaining the increased susceptibility of the heavy drinker to the toxicity of anesthetics, commonly used medications (i.e. isoniazid), analgesics (i.e. acetaminophen), and chemical carcinogens. Induction of microsomal enzymes also contributes to vitamin A depletion, enhances its hepatotoxicity and results in increased acetaldehyde generation from ethanol, with formation of protein adducts, glutathione depletion, free-radical-mediated toxicity, and lipid peroxidation. Chronic ethanol consumption strikingly enhances the number of hepatic collagen-producing activated lipocytes. Both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and activated lipocytes) ethanol and/or its metabolite acetaldehyde increase collagen accumulation and mRNA for collagen. Gender differences are related, in part, to lower gastric ADH activity (with consequent reduction of first pass ethanol metabolism) in young women, decreased hepatic fatty acid binding protein and increased free-fatty acid levels as well as lesser omega-hydroxylation, all of which result in increased vulnerability to ethanol. Elucidation of the biochemical effects of ethanol are now resulting in improved therapy: in baboons, S-adenosyl-L-methionine attenuates the ethanol-induced glutathione depletion and associated mitochondrial lesions, and polyenylphosphatidylcholine opposes the ethanol-induced hepatic phospholipid depletion, the decrease in phosphatidylethanolamine methyltransferase activity and the activation of hepatic lipocytes, with full prevention of ethanol-induced septal fibrosis and cirrhosis; its dilinoleoyl species also increases collagenase activity in lipocytes. The efficacy of this compound in man is now being studied in randomized multicenter clinical trials.
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PMID:Susceptibility to alcohol-related liver injury. 897 51

Alcohol-induced tissue damage results from associated nutritional deficiencies as well as some direct toxic effects, which have now been linked to the metabolism of ethanol. The main pathway involves liver alcohol dehydrogenase which catalyzes the oxidation of ethanol to acetaldehyde, with a shift to a more reduced state, and results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver. More severe toxic manifestations are produced by an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (2E1). After chronic ethanol consumption, there is a 4- to 10-fold induction of 2E1, associated not only with increased acetaldehyde generation but also with production of oxygen radicals that promote lipid peroxidation. Most importantly, 2E1 activates many xenobiotics to toxic metabolites. These include solvents commonly used in industry, anaesthetic agents, medications such as isoniazid, over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamin A and its precursor beta-carotene. Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology. Induction of 2E1 also yields increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. New therapies include adenosyl-L-methionine which, in baboons, replenishes glutathione, and attenuates mitochondrial lesions. In addition, polyenylphosphatidylcholine (PPC) fully prevents ethanol-induced septal fibrosis and cirrhosis, opposes ethanol-induced hepatic phospholipid depletion, decreased phosphatidylethanolamine methyltransferase activity and activation of hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity. Current clinical trials with PPC are targeted on susceptible populations, namely heavy drinkers at precirrhotic stages.
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PMID:Ethanol metabolism, cirrhosis and alcoholism. 902 26

The purpose of this study was to investigate the in vitro degradation potential of porcine pericardia fixed with various aldehyde or epoxy compound (EC) fixatives, using bacterial collagenase and pronase. The fixatives investigated were formaldehyde (FA), glutaraldehyde (GA), monofunctional EC (EX-131), and multifunctional ECs (EX-810, EX-313, and EX-512). Fresh porcine pericardium was used as a control. The test samples were well immersed in a 20-U/mL collagenase solution or a 10-U/mL pronase solution and incubated at 37 degrees C at pH 7.5 for 24 h. The extent of degradation of each test sample was determined by measuring its increment in free amino group content and changes in collagen structure, denaturation temperature, and tensile stress after degradation. In general, the extent of tissue degradation with pronase was more notable than with collagenase. As observed with fresh tissue, the EX-131 EC fixed tissue radically disintegrated after either collagenase or pronase degradation, whereas the other test samples remained intact. The reason for this may reside in the more random molecular packing of the EX-131 EC-fixed tissue, which led to some loss in its helical integrity. This made penetration of enzymes into biological tissue easier. Of the multifunctional EC test groups, tissues fixed with tetrafunctional EC (EX-521) or trifunctional EC (EX-313) had relatively better resistance to degradation than those fixed with bifunctional EC (EX-810). The extent of degradation for the EX-313 or EX-512 EC fixed tissues was similar to that observed for the FA- or GA-fixed tissues. The results of this study indicated that the biological tissue fixed with monofunctional EC (EX-131) cannot resist bacterial collagenase or pronase degradation. However, resistance to degradation of the multifunctional EC (EX-313 or EX-152)-fixed tissues was comparable to that of the aldehyde (FA or GA)-fixed tissues. Therefore, of various EC fixatives, the EC with a greater number of functional groups should be chosen for tissue fixation to increase its resistance to enzymatic degradation.
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PMID:Degradation potential of biological tissues fixed with various fixatives: an in vitro study. 913 63

Acetaldehyde stimulates collagen synthesis in stellate cells and forms adducts with procollagen in the liver of alcoholics. To assess the possibility that modification of the carboxyl-terminal propeptide by acetaldehyde affects its capacity to exert a feedback inhibition of collagen synthesis after splitting from procollagen, the propeptide was prepared by gel filtration of the bacterial collagenase digests of procollagen type I (obtained from 10(9) calvaria fibroblasts of newborn rats) and reacted with either 250 mM acetaldehyde and 100 mM CNBH3 or with 170 microM acetaldehyde without reducing agents, to mimick in vivo conditions. The unmodified propeptide produced a concentration-dependent inhibition of collagen synthesis by Ito cells. By contrast, the acetaldehyde-modified propeptide produced a lesser inhibition of procollagen synthesis in the cells, associated with a greater accumulation of collagen in the media. The incubation with 170 microM acetaldehyde and, to a lesser extent, 50 mM ethanol produced collagenase-digestible adducts in stellate cells. Thus, the formation of acetaldehyde adducts with the carboxyl-terminal propeptide of procollagen may account, at least in part, for the stimulatory effect of acetaldehyde on collagen synthesis by stellate cells and may lead to collagen accumulation through a decrease of the normal feedback regulation of collagen synthesis by the propeptide.
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PMID:Collagen synthesis by liver stellate cells is released from its normal feedback regulation by acetaldehyde-induced modification of the carboxyl-terminal propeptide of procollagen. 934 80

Effect of cigarette smoke on collagen crosslinking was studied in male albino rat skins. Skin samples taken for the analysis on 120th day of exposure to cigarette smoke showed that, compared to controls, the exposed animal had a decreased tendency in the percent reversibility of neutral salt soluble collagen gel, susceptibility of insoluble collagen to denaturing agents and bacterial collagenase. Electrophoresis on SDS-polyacrylamide gel revealed a marked increase in the beta components of the collagen of the rats exposed to cigarette smoke (5.34%) and an appreciable decrease in the ratio of alpha/beta (7.78%). An increase in the aldehyde content of neutral salt soluble collagen was also noticed (32.11%). These changes collectively could indicate the increased crosslinking of dermal collagen in cigarette smoke exposed rats.
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PMID:Influence of cigarette smoke on cross-linking of dermal collagen. 937 18

Chronic liver disease evaluation is a very complicated process requiring complex assessment of numerous liver functions. In addition to standard methods of investigation we perform biotransformation liver tests for evaluation of microsome enzyme system. Markers of fibrogenesis represent modern noninvasive tests for fibrotic liver process detection in different diseases. The key role in the process of fibrogenesis have the adipose liver cells (ITO cells) producing collagen I, III, IV and lamilin. These cells may be transformed into myofibroblasts-like cells under specific conditions. Kupffer cells and monocytes produce substances stimulating the proliferation and transformation of liver ITO cells as also proteoglycans and hyaluronic acid synthesis. Mediators of this fibrogenetic activity are platelet derived growth factor (PDGF), transforming growth factors alpha and beta, lymphokines and monokines released by T-lymphocytes and macrophages, interleukin 1-alpha and interferon-tau. Acetaldehyde and its metabolites are important stimulators of collagen production by liver fibroblasts. The most often used markers of hepatic fibrogenesis are the following: procollagen III peptide, procollagen IV. type (one of its end carboxypeptide chains is determined-either with 7s collagen or NC1), hyaluronic acid, fibronectin, tenascine and unduline. As the most sensitive markers of fibrinogenesis are considered: hyaluronic acid, laminine, procollagen IV. type. Less often used are enzymes participating in collagen synthesis: prolyl-4-hydroxylase,lysyl-hydroxylase, galactosyl-hydroxylysyl-glucosyl-transferase, monoaminooxidase and N-acetyl-beta-D-glucoseaminidase. Breakdown of collagen is a multienzymatic process, catalysed by collagenases and other proteolytic enzymes. Decreased activity of collagenase is a supporting factor of cirrhosis development. Cirrhosis may be connected also with the levels of inhibitors such as e.g. serum/tissue? inhibitor of metalloproteinase. Biochemical markers of fibrogenesis are useful in regular monitoring of disease development and treatment effectivness and should be an inseparable part of progression assessment in all chronic hepatopathies. (Fig. 3, Ref. 49.)
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PMID:[Biochemical markers of fibrogenesis in liver diseases]. 1049 95


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