Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A proportionate mortality ratio (PMR) analysis of all deaths recorded from 1975 to 1985 among New Hampshire white male residents (age 20 years or older) was performed using death certificate information. Among automobile mechanics, the analysis revealed increases in mortality from leukemia (PMR = 178, N = 6); cancers of the oral cavity (PMR = 163, N = 4), lung (PMR = 112, N = 36), bladder (PMR = 169, N = 5), rectum (PMR = 182, N = 4), and lymphatic tissues (PMR = 200, N = 6); and cirrhosis of the liver (PMR = 140, N = 13) and suicide (PMR = 177, N = 22; p less than 0.05). Workers in the gasoline service station industry experienced a leukemia mortality excess (PMR = 328, N = 3; p less than 0.05) as well as increases in deaths from suicide (PMR = 162, N = 4), emphysema (PMR = 245, N = 4), and mental and psychoneurotic conditions (PMR = 394, N = 3). These workers are potentially exposed to a variety of substances including gasoline vapor, benzene, solvents, lubricating oils and greases, and asbestos (from brake and clutch repair) as well as welding fumes and car and truck exhaust. Despite limitations regarding the small number of deaths and methodologic constraints, the results of this analysis suggest that one or more of the exposures experienced by these workers poses a significant carcinogenic risk. More definitive epidemiologic studies are required to determine if the leukemia excess is associated with exposure to benzene, gasoline, or other workplace substances.
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PMID:Proportionate mortality ratio analysis of automobile mechanics and gasoline service station workers in New Hampshire. 361 3

Cytochrome P4502E1 (CYP2E1) activates carcinogenic N-nitrosamines, benzene, urethane and other low molecular weight compounds. This enzyme is also inducible by ethanol, and metabolizes alcohol. A restriction fragment length polymorphism (RFLP) using the Rsa I restriction enzyme has been identified in the CYP2E1 transcription regulatory region; recent studies suggest that this polymorphism may affect gene expression. We investigated the frequency of the Rsa I RFLP in a Japanese population in relation to gastric cancer and liver disease susceptibility. The frequency of this polymorphism was determined in 150 gastric cancer, 16 hepatocellular cancer, 48 liver cirrhosis and 203 benign gastric disease (controls) patients. This preliminary study shows no association of the specific genotype with gastric cancer in all subjects (odds ratio = 1.04, 95% CI = 0.74-3.08 for the heterozygote and 0.57, 95% CI = 0.22-1.50 for the homozygous rare allele, respectively). To further confirm this lack of association, an age and gender matched case-control study should be performed. Separately, there was no association of the Rsa I RFLP with hepatocellular carcinoma (p = 0.911), but there was a suggested difference between the non-viral associated liver cirrhosis patients and control patients. Thus, this polymorphism may be related to ethanol metabolism and consequential liver diseases in a Japanese population.
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PMID:Cytochrome P4502E1 (CYP2E1) genetic polymorphism in a case-control study of gastric cancer and liver disease. 758 84

It has been suggested that organic solvent exposure may contribute to an increased risk of blood disorders, neurological, liver and renal disease, and cancer. A meta-analysis has been performed of 55 published mortality studies which involved solvent exposure and provided standardised mortality ratios (SMR) or relative risk (RR). The combined results showed the overall SMR to be 86.7 (95% confidence interval [Cl] = 83.7-89.9), while that for all sites of cancer was 92.3 (Cl = 87.5-97.4). Risk of death from leukaemia was increased (SMR = 112.2, Cl = 101.6-146.9) as was that from cancer of liver and biliary passages (SMR = 119.7, Cl = 104.4-137.2), even though the risk of death from cirrhosis was reduced (SMR = 81.5, Cl = 68.1-97.4). No excess risk of death from other diseases has been found. The favourable mortality might be from a "healthy worker effect', but the increase in death from liver cancer in the absence of excess deaths from cirrhosis is biologically plausible and justifies further investigation. The increase in mortality from leukaemia is likely to have been associated with exposure to benzene.
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PMID:A meta-analysis of mortality among workers exposed to organic solvents. 891 47

To assess risks of cancer mortality among workers exposed to paints, published papers referring to painters and mortality with standardized mortality ratios (SMR) were meta-analyzed in fixed and random effect models. The SMR for all sites of cancer was significantly raised (111.4; 95% CI: 105.8-117.4). The highest risks of cancer death were from leukemia (187; 95% CI: 114.5-306.7) and from liver cancer (143.6; 95% CI: 117.6-175.4). The SMRs for esophagus and stomach cancer were 132.7 (95% CI: 112.1-157.2) and 120.3 (95% CI: 111.3-130.0), respectively. The risks of bladder cancer (130.4; 95% CI: 113.8-149.5) and lung cancer (129.1; 95% CI: 119.2-139.8) were also raised. The findings provide evidence of an association between work as a painter and risk of cancer, although the confounding effects of smoking and alcohol cannot be entirely excluded, especially with respect to liver cancer since deaths from cirrhosis were also increased. The excess deaths from leukemia could have been from exposure to benzene mixed with other organic solvents, while that from lung cancer may be from exposure to particles containing lead chromate and to asbestos in the paint trade. The high risks of cirrhosis and liver cancer need to be examined further as to possible interactions between organic solvents and alcohol.
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PMID:A meta-analysis of painting exposure and cancer mortality. 982 76

Lentiviral vectors have been used for gene transfer into the liver, but the ability of these vectors to efficiently transduce quiescent hepatocytes remains controversial. Regardless, lentivirus-mediated gene transfer is greatly enhanced when delivered during hepatocellular cycling. For this reason, the present study was designed to determine the role of hepatocyte proliferation in the enhancement of lentiviral transduction by using three different modes of liver regeneration: (1) compensatory regeneration stimulated by two-thirds partial hepatectomy, (2) direct hyperplasia after intragastric administration of the primary mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), and (3) a combination of modes 1 and 2. Vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped lentiviral vector expressing beta-galactosidase was administered to mice via the peripheral circulation after a regeneration stimulus. Gene transfer as measured by 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-Gal) staining showed 30-fold higher levels of liver transduction in groups 1 and 2 as compared with the non-liver-manipulated control group (p < 0.005). The combination of TCPOBOP and partial hepatectomy (group 3) resulted in an ~80-fold increase in transduction efficiency compared with the control animals. The enhanced transduction was consistent with higher levels of hepatocellular proliferation observed in animals that received both treatments compared with either single treatment alone. Importantly, the hepatocytes were the predominant cell type transduced, although transgene expression was observed in a low number of nonparenchymal cells regardless of which liver stimulus was received. Biodistribution studies confirmed that most of the gene transfer was limited to the liver and spleen. Taken together, this study suggests that disease-induced cellular proliferation in the liver will enhance the utility of this vector in treating diseases such as viral hepatitis, liver cirrhosis, and cancer.
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PMID:Role of hepatocyte direct hyperplasia in lentivirus-mediated liver transduction in vivo. 1191 88

BALB/c Fech(m1Pas) mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism (Alas1 and Hmox1, respectively) were only modestly affected even in the presence of the cytochrome P450-inducing CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. In contrast, in BALB/c mice exhibiting griseofulvin-induced hepatic protoporphyria with induction and destruction of cytochrome P450, both Alas1 and Hmox1 genes were markedly up-regulated. Other expression profiles in BALB/c Fech(m1Pas) mice identified roles for oxidative mechanisms in liver injury while modulated gene expression of hepatocyte transport proteins and cholesterol and bile acid synthesis illustrated the development of cholestasis. Subsequent inflammation and cirrhosis were also shown by the up-regulation of cytokine, cell cycling, and procollagen genes. Thus, gene expression profiles studied in Fech(m1Pas) mice may provide candidates for human polymorphisms that explain the sporadic hepatic consequences of erythropoietic protoporphyria.
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PMID:Hepatic gene expression in protoporphyic Fech mice is associated with cholestatic injury but not a marked depletion of the heme regulatory pool. 1579 85

The analysis of the glue "RAZI" was carried out at the Republican Chromatographic Center of Georgia, with high-efficient liquid chromatographic equipment "Millipore Waters" (USA), by I. Wagner's Method. We were able to determine presumable composition of the glue chemical components. The different substances were evaporated at different times fixed by appropriate peaks on chromatogram. There have been at least five toxic substances identified within the glue composition, which are used as industrial or household chemical goods and as some authors explain, may be used as inhaling psychoactive substances. These substances are: benzol (benzene), toluene (toluol), phenol (carbolic acid), chloroform, and methyl-ketone. The glue is inhaled with a small polyethylene bag. The substances are evaporated during inhalation and join arterial blood through lungs. In several minutes leap forward a situation similar to alcohol intoxication. The evaporated substances characterized by strong toxicity and influence to the organism in different ways. The results of chronic glue abuse is serious, such as lethal aplastic anemia, leukemia, marrow damage, chromosome aberrations, functional disorders of CNS, dystrophic changes in myocardium, cirrhosis, liver atrophy and so on. Abuse of the glue "RAZI" can lead to very serious medical consequences and represents emerging public health problem in Georgia.
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PMID:Study of chemical composition of glue "RAZI" used by solvent abusers in Tbilisi. 1670 32

Cytochrome P-450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of a variety of toxicants including nitrosamines, benzene, vinyl chloride, and halogenated solvents such as trichloroethylene. CYP2E1 is also one of the enzymes that metabolizes ethanol to acetaldehyde, and is induced by recent ethanol ingestion. There is evidence that interindividual variability in the expression and functional activity of this cytochrome (CYP) may be considerable. Genetic polymorphisms in CYP2E1 were identified and linked to altered susceptibility to hepatic cirrhosis induced by ethanol and esophageal and other cancers in some epidemiological studies. Therefore, it is important to evaluate how such polymorphisms affect CYP2E1 function and whether it is possible to construct a population distribution of CYP2E1 activity based upon the known effects of these polymorphisms and their frequency in the population. This analysis is part of the genetic polymorphism database project described in the lead article in this series and followed the approach described in that article (Ginsberg et al., 2009, this issue). Review of the literature found that there are a variety of CYP2E1 variant alleles but the functional significance of these variants is still unclear. Some, but not all, studies suggest that several upstream 5' flanking mutations affect gene expression and response to inducers such as ethanol or obesity. None of the coding-region variants consistently affects enzyme function. Part of the reason for conflicting evidence regarding genotype effect on phenotype may be due to the wide variety of exposures such as ethanol or dietary factors and physiological factors including body weight or diabetes that modulate CYP2E1 expression. In conclusion, evidence is too limited to support the development of a population distribution of CYP2E1 enzyme activity based upon genotypes. Health risk assessments may best rely upon data reporting interindividual variability in CYP2E1 function for input into physiologically based pharmacokinetic (PBPK) models involving CYP2E1 substrates.
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PMID:Genetic polymorphism in CYP2E1: Population distribution of CYP2E1 activity. 2018 27

The proliferative response of hepatocytes in vivo can be induced by two mechanisms: severe damage to hepatic tissue results in regenerative growth and so-called primary hepatocyte mitogens can initiate liver cell proliferation without preceding loss of parenchyma. The regulation of the two responses is quite different. The decreased regenerative response of cirrhotic/fibrotic liver is well known, and is a severe obstacle to surgery of the diseased liver. In the present experiments we investigated the efficiency of a primary hepatocyte mitogen 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOB) on two different liver cirrhosis/fibrosis models in mice induced by chronic administration of CCl(4) and thioacetamide respectively. BrdU incorporation and cyclin A expression established clearly that there is a reduced but still powerful mitogenic response of the fibrotic livers. Therefore, primary hepatocyte mitogens appear to be suitable to be used to rescue the regenerative response of cirrhotic livers.
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PMID:1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene induces substantial hyperplasia in fibrotic mouse liver. 2224 68

Although not mutagenic by Ames test, 2,5-dimethylfuran (DMF), a leading biofuel candidate, was found to induce chromosomal damage in cultured murine cells, suggesting that it may be genotoxic. We sought to prioritize the environmental and biological impacts of using DMF as a combustible biofuel. First, we assessed DMF and its combustion intermediates for potential persistence, bioaccumulation, and aquatic toxicity (PBT) using PBT profiler. Our findings predict DMF to have moderate-level aquatic toxicity; however, a greater subset of the combustion intermediates is predicted to have moderate- and high-level aquatic toxicity with bioaccumulation and persistence concerns. Second, we assessed the biological impact of DMF by testing for statistically significant chemical-disease associations. No direct associations for DMF were found; however, indirect associations were identified from two structurally similar analogs. Curated associations between furfuryl alcohol to kidney neoplasm and adenoma, and significant inferred associations between furan to lung neoplasm, drug-induced liver injury, and experimentally induced liver cirrhosis were found, based on 21 furan-gene interactions. Nine of 49 DMF combustion intermediates analyzed, including benzene and 1,3-butadiene, were found to have associations with 26 tumors and systemic diseases. Although inadequate for a stand-alone risk assessment, our data suggest that DMF combustion intermediates pose a much broader range of hazards than DMF itself, and that both should be further investigated.
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PMID:Predicted toxicity of the biofuel candidate 2,5-dimethylfuran in environmental and biological systems. 2273 Jan 90


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