Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Priming of the liver for ethanol-induced injury, by nutrients such as polyunsaturated fat and iron, plays a key role in alcoholic liver disease. The objective of this work was to evaluate the effect of the combination of Fe-nitrilotriacetic acid (Fe-NTA) and arachidonic acid (AA) on the viability of HepG2 cells (E47 cells) transfected to express human CYP2E1. Cells were plated, preloaded with arachidonic acid, washed, and exposed to Fe-NTA for variable periods. Fe-NTA (10 microM) or AA (5 microM) alone showed low toxicity to E47 cells (18 and 8%, respectively, at 24 h), whereas the combination produced synergistic injury (62% toxicity at 24 h). Exposure of cells not expressing any cytochrome P450 (P450), or HepG2-C3A4 cells (expressing CYP3A4) to 10 microM Fe-NTA plus 5 microM AA produced lower toxicity (14 and 32%, respectively), demonstrating a role for P450, and in particular CYP2E1, in the development of toxicity by exposure to Fe + AA. Lipid peroxidation was induced in the E47 cells exposed to Fe plus arachidonic acid and the synergistic toxicity was prevented by antioxidants, which also decreased lipid peroxidation. Damage to mitochondria plays a role in the CYP2E1-dependent toxicity of Fe + AA, because the mitochondrial transmembrane potential decreased early in the process, and cyclosporin A prevented the toxicity. Toxicity in E47 cells exposed to Fe + AA is mainly necrotic in nature. Hepatocytes from pyrazole-treated rats, with high levels of CYP2E1, were more sensitive to Fe + AA toxicity than were saline control hepatocytyes. The results presented suggest that low concentrations of Fe and AA can act as priming or sensitizing factors for CYP2E1-induced injury in HepG2 cells, and such interactions may play a role in alcohol-induced liver injury.
Mol Pharmacol 2001 Oct
PMID:Synergistic toxicity of iron and arachidonic acid in HepG2 cells overexpressing CYP2E1. 1156 36

The intragastric tube feeding model of alcoholic liver disease in the rat induces significant liver histopathology, including steatohepatitis and fibrosis. The question is, if the same low-carbohydrate diet is fed ad lib, will the same pathology develop? Rats were fed a liquid diet with ethanol ad lib that was low in calories derived from carbohydrates for 2 months. The urinary ethanol levels (UALs) were monitored at hourly, daily, and weekly intervals, and the growth of the rats was charted. The liver histopathology and blood transaminase levels were determined. Rats fed ethanol grew 1 g/day, which was 2 g/day less than when they were fed the same diet intragastrically. UALs varied hourly between 150 and 500 mg%, daily between 120 and 360 mg%, and weekly between 0 and 500 mg%. Individual rat UALs showed no predictable pattern. The pair-fed controls ate all of their daily ration within 12 h, then fasted until the next day. The histopathology and blood alanine aminotransferase were similar to those seen with the intragastric tube feeding of the same diet, except that necrosis, inflammation, and fibrosis did not develop. The conclusion was that the oral feeding of a low-carbohydrate diet produces less liver injury than that produced by the same diet fed intragastrically. The UALs varied hourly, daily, and weekly in individual rats, making it difficult to synchronize UALs at the time of sacrifice.
Exp Mol Pathol 2001 Oct
PMID:Oral low-carbohydrate alcohol liquid diet induces experimental steatohepatitis in the rat. 1159 19

The hepatitis B virus X protein (HBx) plays essential roles in viral replication and the generation of hepatocellular carcinoma. In spite of a large number of suggestive cellular targets and functions, a clear picture of its mechanism(s) of action has remained elusive. In this report, we continue to characterize its recently described mitochondrial association and further examine its impact on mitochondrial functions. HBx was previously shown to bind to a voltage-dependent anion channel (VDAC3) and alter the mitochondrial transmembrane potential (Delta Psi(m)). Here we show that, as a consequence of association with mitochondria, HBx constitutively induces activation of transcription factors, which include STAT-3 and NF-kappa B. This induction of activation was sensitive to the antioxidants N-acetyl L-cysteine and pyrrolidine dithiocarbamate, as well as to overexpression of Mn-superoxide dismutase. These results therefore implicate a potential role of reactive oxygen species (ROS) in a process that ultimately leads to the activation of STAT-3 and NF-kappa B. Evidence is also presented for the HBx-induced generation of ROS. The ability of HBx to induce the activation of STAT-3 and NF-kappa B was demonstrated by mobility shift and reporter gene expression assays with lysates from HBx-transfected HepG2 cells. A C-terminal HBx deletion mutant, HBx Delta 99, failed to bind VDAC3 and activate STAT-3 and NF-kappa B. These studies shed new light on the physiological significance of HBx's mitochondrial association and its role in inducing oxidative stress which can contribute to the liver disease pathogenesis associated with the hepatitis B virus infection.
Mol Cell Biol 2001 Nov
PMID:Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. 1160 8

Hepatitis C virus (HCV) chronically infects at least 1% of the world's population and is a leading cause of end-stage liver disease. HCV displays a remarkable degree of genomic diversity, with the six major genotypes and numerous subtypes differing in geographic distribution. The ability of this virus to cause persistent infections is a direct result of its genomic plasticity and the evolution of quasispecies within an infected individual. HCV genotype has emerged as an important factor both in predicting a sustained response to, and in determining the duration of, antiviral therapy. Although a variety of methods have been used for genotyping HCV, nucleotide sequencing of a phylogenetically informative region remains the gold standard.
Mol Diagn 2001 Dec
PMID:Hepatitis C virus genotyping: clinical implications and methods. 1177 92

The aetiological agent of chronic hepatitis C is the hepatitis C virus. The hepatitis C virus is spread by parenteral transmission of body fluids, primarily blood or blood products. In 1989, after more than a decade of research, HCV was isolated and characterised. The hepatitis C viral genome is a positive-sense, single-stranded RNA molecule approximately 9.4 kb in length, which encodes a polyprotein of about 3100 amino acids. There are 6 main genotypes of HCV, each further stratified by subtype. In 1994, a cohort of women was identified in Ireland as having been iatrogenically exposed to the hepatitis C virus. The women were all young and exposed as a consequence of the receipt of HCV 1b contaminated anti-D immunoglobulin. The source of the infection was identified as an acutely infected female. As part of a voluntary serological screening programme involving 62,667 people, 704 individuals were identified as seropositive for exposure to the hepatitis C virus; 55.4% were found to be positive for the viral genome 17 years after exposure. Of these women 98% had evidence of inflammation, but surprisingly, a remarkable 49% showed no evidence of fibrosis. Clinicopathology and virological analysis has identified associations between viral load and the histological activity index for inflammation, and, between inflammation and levels of the liver enzyme alanine aminotransferase. Infection at a younger age appears to protect individuals from progression to advanced liver disease. Molecular analyses of host immunogenetic elements shows that particular class II human leukocyte associated antigen alleles are associated with clearance of the hepatitis C virus. Additional class II alleles have been identified that are associated with stable viraemia over an extended period of patient follow-up. Although, investigation of large untreated homogeneous cohorts is likely to become more difficult, as the efficacy of anti-viral therapy improves, further investigation of host and viral factors that influence disease progression will help provide an evidence based approach were realistic expectations regarding patient prognosis can be ascertained.
Int J Mol Med 2002 Feb
PMID:The Irish paradigm on the natural progression of hepatitis C virus infection: an investigation in a homogeneous patient population infected with HCV 1b (review). 1178 30

In this study the authors applied a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect hepatitis C virus (HCV) RNA in 15 frozen liver biopsy samples from anti-D-treated patients. They also correlated the presence or absence of HCV RNA in the serum and liver of each patient with their histologic gradings. RNA was extracted from 36 frozen liver biopsy samples. These included 15 liver biopsy samples from patients infected with HCV through contamination of anti-D blood products. Three of these 15 anti-D-treated patients were receiving alpha-interferon treatment at the time of liver biopsy. Nine frozen liver biopsy samples from patients with a history of intravenous drug abuse were included as positive controls. HCV-negative frozen liver biopsy samples from 12 noninfected patients were used as negative controls. RNA was also extracted from six frozen skin biopsy specimens to check for cross-contamination of samples. Eleven of 15 anti-D-treated patients were HCV RNA positive by RT-PCR, with 100% correlation between HCV RNA in the serum and liver. The nine frozen liver biopsy samples from the intravenous drug abuse patients (positive controls) were also RT-PCR positive for HCV RNA. The 12 noninfected samples and the negative control biopsy samples were negative for HCV. Twenty-seven percent of the recombinant immunoblot assay-positive patients were serum and liver HCV RNA negative. HCV-positive patients receiving alpha-interferon therapy at the time of biopsy had cleared the virus from the serum and the liver. There was no correlation between the presence or absence of serum and liver HCV RNA with the histologic grading. This lack of correlation shows clearly the importance of histopathologic evaluation of liver biopsy samples in monitoring HCV-associated liver disease progression. In addition, this finding indicates that one cannot rely only on the presence or absence of HCV RNA in either serum or liver tissue as a parameter in monitoring HCV-associated liver disease progression in this unique cohort of anti-D-treated patients.
Diagn Mol Pathol 2002 Mar
PMID:Lack of association between hepatitis C viral RNA in serum and liver and histologic gradings: a study on Irish anti-D-treated patients. 1185 99

Pediatric autoimmune liver disease is mainly represented by two similar liver disorders: autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), both characterized by hypergammalobulinemia, interface hepatitis and the presence of a wide range of circulating autoantibodies. Although similar features are seen in AIH and inflammatory bowel disease, histological biliary changes are more common in ASC. In addition to their role as diagnostic markers, autoantibodies, such as anti-extractable nuclear antigen (ENA) antibodies and liver kidney microsomal antibody type 1 (LKM1) may be involved directly in inducing aggressive liver diseases. Although the cellular immune response in pediatric autoimmune liver disease has been less intensively investigated than humoral immunity, the importance of antigen specific T cells has been explored. Both alphabeta and gammadelta T cells derived from either peripheral blood and liver biopsies have highly heterogeneous TCR gene usage and cytolytic activity has been demonstrated. There have been attempts to seek triggers of liver autoimmunity and several sequences shared in common between autoantigens and hepatotropic viruses, namely hepatitis B, C and cytomegalovirus have been identified. The presence of cross-reactivity between homologous sequences, especially between HCV and cytochromes, supports the possibility that molecular mimicry plays a role in the induction of autoantibodies and autoreactive cytotoxic T cells.
Curr Mol Med 2001 Jul
PMID:Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity. 1189 84

Studies of animal models suggest that the activation of soluble guanylate cyclase by nitric oxide is altered in liver disease. We studied 77 patients with liver disease and 17 controls, to investigate whether the activation of soluble guanylate cyclase is altered in lymphocytes from patients with liver disease. The basal content of guanosine 3',5'-cyclic monophosphate (cGMP) in lymphocytes was decreased both in patients with liver cirrhosis (by 52%) and in patients with chronic hepatitis (by 62%). Activation of soluble guanylate cyclase by nitric oxide was higher in lymphocytes from patients with cirrhosis (3100+/-1000% of basal) or with hepatitis (5200+/-2500% of basal) than in lymphocytes from controls (1200+/-500% of basal). cGMP in plasma was increased in patients with liver disease. Successful (but not unsuccessful) treatment with interferon of patients with hepatitis due to virus C reversed all the above alterations. Altered modulation of soluble guanylate cyclase by nitric oxide in liver disease may play a role in the hemodynamic alterations found in these patients.
J Mol Med (Berl) 2002 Feb
PMID:Altered modulation of soluble guanylate cyclase in lymphocytes from patients with liver disease. 1190 48

A deficiency of ferrochelatase (FECH) activity underlies the excess accumulation of protoporphyrin that occurs in erythropoietic protoporphyria (EPP). In some patients, protoporphyrin accumulation causes liver damage that necessitates liver transplantation. The purpose of this study was to determine if specific mutations in the FECH gene are present in patients who develop liver disease. FECH cDNA and all 11 exons and their flanking intron regions in the FECH gene were amplified and sequenced by specific polymerase chain reactions. Gene mutations were determined in 34 individuals from 24 families: 14 had liver disease, 10 necessitating liver transplantation. All individuals were heterozygous for mutations that altered the coding region of FECH mRNA. The mutations in patients with liver disease were heterogenous, but usually caused a major structural alterations in the FECH protein, most commonly as a result of exon skipping in FECH mRNA. However, the mutations could not account for the severe phenotype by themselves, since the same mutations were found in asymptomatic family members of patients with liver disease and in patients from families in which liver disease was not present. Other genetic factors, and possibly acquired factors, also must be critical to the development of this severe phenotype in EPP.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Ferrochelatase gene mutations in erythropoietic protoporphyria: focus on liver disease. 1192 52

Erythropoietic protoporphyria (EPP), an inborn error of heme metabolism, causes in the majority of the patients only a symptom of photosensitivity. However, around 2% of the EPP sufferers develop liver complication in the form of liver cirrhosis and progressive liver failure. Mutations in the human ferrochelatase (FECH) gene causing EPP are highly heterogeneous and mostly family-specific. Actually, 62 FECH mutations have been published, 48 of them are "null allele" mutations inducing the formation of a truncated protein. The remaining 14 are missense mutations. In contrast to the null allele mutations, the latter lead to substitution of a single amino acid residue in the protein molecule and generate an enzyme that, although functionally impaired, is in its full length. In order to study the association between "null allele" mutation and liver complication, we combined our data with those in the literature. A total of 112 EPP patients were counted among 93 EPP families with a known FECH mutation. All 18 EPP patients who had severe liver complication carried a "null allele" mutation. In contrast, none of the 20 patients who carried a missense mutation had developed liver complication till the time of study (Fisher's exact test, p<0.05). High protoporphyrin blood concentration are considered to be a sign of an increased risk of liver disease. No correlation of protoporphyrin blood level with the type of mutation, was found, if patients with overt liver disease were excluded from the sample. Furthermore, no significant association of the liver complication with the location of the mutation within the FECH gene was found (Fisher exact test p = 0.46). These available data indicate a significant genotype-phenotype correlation between "null allele" mutation and protoporphyrin related liver disease in EPP. Although the risk for a EPP patient with a missense mutation to develop liver disease cannot be totally eliminated based on these data, it is comparably low.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:A genotype-phenotype correlation between null-allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria. 1192 53


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