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)

Altered degradation of extracellular matrix has been implicated in the pathogenesis of hepatic fibrosis. We studied the effect of acetaldehyde (AcCHO) on gene expression of matrix-metalloproteinase (MMP)-1 (fibroblast type- interstitial collagenase) and MMP-2 (72 kDa gelatinase-type IV collagenase) in comparison with the AcCHO effect on collagen type I and IV synthesis in cultures of fat-storing cells (FSC) isolated from normal human livers. Cultured human FSC expressed single mRNA transcripts (2.7 and 3.2 kb) specific for MMP-1 and MMP-2, respectively. AcCHO inhibited MMP-1 mRNA levels, whereas it stimulated collagen type I mRNA and protein expression. Opposite AcCHO effects were evident on MMP-2 mRNA and collagen IV synthesis, being MMP-2 up-regulated and collagen IV down-regulated. These data suggest that regulation of MMP-1 and MMP-2 genes by AcCHO may contribute to disruption of the normal basement membrane and its replacement with fibrillar collagens in the early stages of alcoholic liver fibrosis.
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PMID:Acetaldehyde regulates the gene expression of matrix-metalloproteinase-1 and -2 in human fat-storing cells. 793 38

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

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

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

We studied the direct effects of ethanol and its metabolites on the guinea pig lung mast cell, and the alterations caused in the histamine release induced by different stimuli. Guinea pig lungs cells dispersed by collagenase were used throughout. High concentrations of ethanol (100 mg/ml), acetaldehyde (0.3-3 mg/ml) and acetic acid (3 mg/ml) induced histamine release that was not inhibited by sodium cyanide (0.3 mM). Lower concentration of ethanol (10 mg/ml) and acetic acid (0.3 mg/ml), but not acetaldehyde, inhibited the histamine release induced by antigen and ionophore A23187. The histamine release induced by phorbol 12-miristate 13-acetate (1 microM) was also inhibited by ethanol (10 mg/ml). Changes in the levels of calcium, glucose and phosphatidic acid did not influence the effect of ethanol. We conclude that high doses of ethanol, acetaldehyde, and acetic acid cause a cytotoxic histamine release by independent mechanisms. Low concentrations of acetic acid inhibit the histamine release by pH reduction. Ethanol acts by a generalized effect that is independent of calcium and glucose suggesting a nonspecific effect that, nevertheless, is not cytotoxic since it can be reversed by washing the cells.
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PMID:Effects of ethanol, acetaldehyde, and acetic acid on histamine secretion in guinea pig lung mast cells. 1071 92

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.
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PMID:Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. 1567 Jun 59

Blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC) regulates the passage of molecules and leukocytes in and out of the brain. Activation of matrix metalloproteinases (MMPs) and alteration of basement membrane (BM) associated with BBB injury was documented in stroke patients. While chronic alcoholism is a risk factor for developing stroke, underlying mechanisms are not well understood. We hypothesized that ethanol (EtOH)-induced protein tyrosine kinase (PTK) signaling resulted a loss of BBB integrity via MMPs activation and degradation of BM component, collagen IV. Treatment of BMVEC with EtOH or acetaldehyde (AA) for 2-48 h increased MMP-1, -2 and -9 activities or decreased the levels of tissue inhibitors of MMPs (TIMP-1, -2) in a PTK-dependent manner without affecting protein tyrosine phosphatase activity. Enhanced PTK activity after EtOH exposure correlated with increased phosphorylated proteins of selective receptor and nonreceptor PTKs. Up-regulation of MMPs activities and protein contents paralleled a decrease in collagen IV content, and inhibitors of EtOH metabolism, MMP-2 and -9, or PTK reversed all these effects. Using human BMVEC assembled into BBB models, we found that EtOH/AA diminished barrier tightness, augmented permeability, and monocyte migration across the BBB via activation of PTKs and MMPs. These findings suggest that alcohol associated BBB injury could be mediated by MMPs via BM protein degradation and could serve as a comorbidity factor for neurological disorders like stroke or neuroinflammation. Furthermore, our preliminary experiments indicated that human astrocytes secreted high levels of MMP-1 and -9 following exposure to EtOH, suggesting the role of BM protein degradation and BBB compromise as a result of glial activation by ethanol. These results provide better understanding of multifaceted effects of alcohol on the brain and could help develop new therapeutic interventions.
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PMID:Activation of protein tyrosine kinases and matrix metalloproteinases causes blood-brain barrier injury: Novel mechanism for neurodegeneration associated with alcohol abuse. 1794 53


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