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

The role of the hepatitis B virus (HBV) X protein in liver tumorigenesis is unresolved. Transgenic mice harboring the X gene (nt 1376-1840 under the control of the human alpha-1-antitrypsin regulatory elements) (ATX mice) display only minor histopathologic alterations of the liver. To determine if ATX mice are more susceptible to the effects of hepatocarcinogens, 12- to 15-d-old male ATX and control littermate mice were injected with a single dose (2 microgram/g body weight) of diethylnitrosamine (DEN). The animals were killed 6-10 mo after exposure and were analyzed for histological changes in the liver. One hundred percent of the DEN-treated AXT mice developed abnormal liver lesions. Then their liver tissues were compared by stereological analysis with those of non-transgenic animals, the ATX mice had a relative twofold increase in the total number of focal lesion and a twofold increase in the incidence of hepatocellular carcinoma. Elevated levels of X protein and p53 protein were not detected in carcinogen-induced nodules or tumors. These results are consistent with a model in which the expression of the HBV X protein potentiates the induction of DEN-mediated liver disease.
Mol Carcinog 1996 Apr
PMID:Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene. 863 84

Perturbations in keratin intermediate filament organization and Mallory body (MB) formation are associated with alcoholic hepatitis. Inducible heat shock proteins (HSPs) are expressed in a variety of liver diseases including alcoholic liver disease. Therefore, we investigated whether heat shock protein induction can lead to MB formation. Mice were primed by a 5-month feeding of griseofulvin (GF) or diethyl 1,4-dehydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) followed by drug withdrawal for 1 month. The animals were then subjected to an in vivo heat shock treatment or sham heat treatment. Liver morphology, HSP expression, liver regeneration (PCNA-labeled nuclei), and MB formation were monitored during a 7-day posttreatment period. Numerous MBs developed in the livers of mice exposed to GF or DDC for 5 months, but very few small MBs remained after 1-month withdrawal of either drug. No MBs were found at Day 1 post heat shock, whereas numerous MBs were observed at Day 7. The frequency of PCNA-labeled nuclei increased during the same period. At Day 1 posttreatment, a variable liver centrilobular necrosis was observed accompanied by a prominent increase in HSP-25 and HSP70 expression, but HSP-90 expression was not increased. In drug-primed mouse liver, a heat shock treatment induces the expression of specific HSPs prior to the formation of MBs, indicating that HSP expression may play a role in the pathogenesis of MB formation. We speculate that this role is through the protein unfolding function of HSP, which leads to the aggregation of the cytokeratins to form MBs as well as to polyubiquitin binding to these proteins in a manner analogous to amyloid formation.
Exp Mol Pathol 1995 Aug
PMID:Heat shock in vivo induces Mallory body formation in drug primed mouse liver. 875 55

In a retrospective long-term follow-up study the clinical course of liver disease was examined in renal allograft recipients with hepatitis C virus (HCV) infection and negative hepatitis B surface antigen under immunosuppressive therapy. We compared 42 anti-HCV antibody (anti-HCV) positive patients (study group) to 213 anti-HCV negative patients (control group). All patients received immunosuppressive therapy. Measurements were made of the following: aminotransferases, bilirubin, albumin, gammaglobulins, ascites, spleen diameter, HCV RNA, and anti-HCV antibody. We found all but four anti-HCV positive patients to be HCV RNA positive prior to transplantation. There were no differences in overall mortality or mortality secondary to liver disease or sepsis. Normal liver enzymes were found in 13 (31%) anti-HCV positive and in 137 (64%) anti-HCV negative patients during the whole mean observation period of 65 months (range 10-215). Aminotransferase activity decreased in anti-HCV positive and negative patients during the observation period. Liver function with regard to synthesis and excretion was normal in anti-HCV negative and anti-HCV positive patients. No signs of portal hypertension were observed in the anti-HCV positive group. Neither the different immunosuppressive regimens nor the antirejection therapy led to differences between anti-HCV positive and negative groups with respect to liver function and did not alter the clinical course. We conclude that HCV infection in patients under immunosuppressive therapy causes only a mild liver disease, as determined by clinicochemical and clinical parameters, and that mortality rate is not increased.
J Mol Med (Berl) 1996 Jul
PMID:Immunosuppressive therapy and hepatitis C virus infection: the clinical course of liver disease. 884 53

The protein binding of felodipine in concentrations ranging from 3 to 65 nmol L-1 has been characterized in pooled serum, and in isolated human plasma proteins: albumin (HSA) and a1-acid glycoprotein (AAG). Protein binding was determined by an ultrafiltration technique using an Amicon Micropartition System. Serum protein binding of felodipine (16 nmol L-1) was measured in five groups of individuals: I: healthy subjects (n = 16). II: patients with chronic renal disease before and after dialysis (n = 10). III: patients with liver disease (n = 9). IV: diabetics Type I (n = 10) and Type II (n = 12) and V: cancer patients (n = 12). Concentrations of HSA, AAG, lipoproteins and non esterified fatty acids (NEFA) were also measured. The drug was extensively bound in pooled serum and the protein binding was essentially unchanged over the concentrations of felodipine studied (99.60 +/- 0.31% at 3 nmol L-1; 99.70 +/- 0.15% at 65 nmol L-1). In albumin solution (40 g L-1) felodipine was also highly bound. The mean of percentage bound was not significantly different from that in serum and was also independent of the felodipine concentrations (98.57 +/- 0.35 at 3 nmol L-1; 98.31 +/- 0.90 at 65 nmol L-1). The extent of binding to AAG was significantly lower than in serum (p < 0.01) and HSA (p < 0.01) and was independent of felodipine concentrations (85.64 +/- 2.25 at 3 nmol L-1; 85.68 +/- 2.3 at 65 nmol L-1). The percentage of bound felodipine in group II (before dialysis) was significantly lower than in group I (p < 0.001). The variability in the percentage of bound felodipine was greater in group II, before dialysis, than in the rest of the groups. After dialysis, protein binding was similar to that in group I. HSA did not change and AAG was increased. NEFA was significantly higher after dialysis when compared with group I (p < 0.01). In vitro carbamylation of serum did not change felodipine protein binding. HSA was decreased significantly in group III patients (p < 0.05). However, protein binding did not change. Binding of felodipine in the rest of the groups was not significantly different from that in group I. Linear regression analysis of the data for all individuals indicated that the binding of felodipine was related to serum lipoproteins and that age, HSA, AAG, and NEFA were not significant determinants of binding.
Res Commun Mol Pathol Pharmacol 1996 Oct
PMID:Characteristics of serum protein binding of felodipine. 894 16

Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. CYP2E1 has also been implicated in alcohol liver disease because of its contribution to oxidative stress. Previously, polymorphic alleles with mutations in introns and in the 5'-flanking regulatory region have been described, and their presence has been related to the incidence of alcohol liver disease and lung cancer. In the present investigation, we investigated whether any functional mutations are linked to the above-mentioned rare alleles and also screened for mutations in the open reading frame using single-stranded conformation polymorphism and genomic DNA from almost 200 individuals belonging to either a Chinese, an Italian, or a Swedish population. Two new CYP2E1 gene variants were found with functional mutations: one (CYP2E1*2) in which a G1168A point mutation in exon 2 caused an R76H amino acid substitution, and the other (CYP2E1*3) in which a G10059A base substitution in exon 8 yielded a V3891 amino acid exchange. The corresponding CYP2E1 cDNAs were constructed, subcloned into the pCMV4 expression vector, and expressed in COS-1 cells. The cellular levels of CYP2E1 mRNA, CYP2E1 protein, and rate of chlorzoxazone hydroxylation were monitored. The CYP2E1*3 cDNA variant was indistinguishable from the wild-type cDNA on all variables investigated, whereas CYP2E1*2 cDNA, although yielding similar amounts of mRNA, only caused 37% of the protein expression and 36% of the catalytic activity compared with the wild-type cDNA. Complete screening by single-stranded conformation polymorphism of the three populations studied revealed that these variant alleles were rare. We conclude that the human CYP2E1 gene is functionally surprisingly well conserved compared with other cytochrome P450 enzymes active in drug metabolism, which suggests an important endogenous function in humans.
Mol Pharmacol 1997 Mar
PMID:Genetic polymorphism of human CYP2E1: characterization of two variant alleles. 905 90

A novel calcium-binding protein regucalcin has been shown to be specifically expressed in the liver of various specifies including human. Regucalcin concentration in the serum of patients with chronic liver injury was estimated by enzyme-linked immunoadsorbent assay (ELISA) with rabbit-anti-regucalcin IgG. Serum samples were obtained from 42 persons who were diagnosed as liver disorder. Serum regucalcin concentration in all patients was in the range of 3.7-69.6 ng/ml, although regucalcin was not entirely seen in the serum of normal subjects (10 persons) without hepatitis. Meanwhile, in 18 patients with liver injury, serum glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) activities were normal value (less than 40 I.U./I). Serum GOT and GPT activities from 24 patients showed a comparatively higher level (50-234 I.U./I). The present results demonstrate the potential sensitivity of regucalcin as a marker of chronic liver injury.
Mol Cell Biochem 1997 Feb
PMID:Potential sensitivity of hepatic specific protein regucalcin as a marker of chronic liver injury. 905 96

The liver is an amazing organ because it can regenerate. The differentiated parenchymal cells, which do not normally divide, can undergo multiple rounds of cellular division. This brings into question the exact role of the liver stem-cell, which has not been fully characterized. The knowledge gained from the dissection of the basic molecular and cellular events that occur during hepatic regeneration will be useful for advancing therapeutic interventions for individuals with liver disease or genetic deficiencies. This article reviews the basic principles of liver regeneration, experimental manipulations in animal models, and human clinical applications including cellular transplantation, gene therapy and artificial livers.
Mol Med Today 1997 Mar
PMID:Liver regeneration: prospects for therapy based on new technologies. 909 85

The histopathologic alterations of hepatitis C virus (HCV) infection of the liver overlap with those of other diseases, making interpretation of liver biopsy specimens in some cases insufficient to render a diagnosis. Although HCV infection can be confirmed by detection of circulating anti-HCV antibodies, immunocompromised liver transplant recipients are often unable to mount an immunologic response to the virus, resulting in false-negative serologic testing. We describe the comparison of reverse transcription-polymerase chain reaction (RT-PCR) with histopathology, serology, and immunohistochemistry for the diagnosis of HCV. Sixty-three formalin-fixed, paraffin-embedded tissue samples (40 needle biopsy specimens and 23 native liver resection specimens) from 35 transplant patients were analyzed by use of a novel method of RNA extraction followed by nested PCR for HCV as well as albumin mRNA as an internal control. HCV was detected by RT-PCR in 50 of 51 (98%) paraffin sections of liver from transplant patients with circulating anti-HCV antibodies, 15 of which lacked characteristic histologic features of HCV infection. Overall, there were no false-negative results in 36 needle biopsy specimens from patients with hepatitis C infection, but three negative results were seen in end-stage cirrhotic native livers resected from HCV-infected patients. No false-positive test results were seen among 21 negative controls (10 liver samples from immunocompetent patients with abnormalities unrelated to hepatitis C and 11 liver biopsies from immunocompetent patients without histologic evidence of liver disease). In comparison, immunohistochemistry using antibody TORDJI-22 was positive for HCV in only 15 of 32 (47%) needle biopsies positive by RT-PCR. Our results indicate that RT-PCR is a more sensitive and specific method of detecting hepatitis C in routinely processed paraffin sections of formalin-fixed liver biopsy specimens than histopathologic examination or immunohistochemistry.
Diagn Mol Pathol 1997 Apr
PMID:Detection of hepatitis C by RT-PCR in formalin-fixed paraffin-embedded tissue from liver transplant patients. 909 52

Hepatic CYP2E1 is induced in several models of alcohol administration, but clinically relevant pathology is only observed in rats in a model involving the continuous intragastric administration of an ethanol-containing, corn oil-based, high-fat diet. The level of CYP2E1 correlates with the degree of liver pathology in the intragastric feeding model, which leads to the hypothesis that radical production by CYP2E1 is responsible for the pathology. Destruction of the Kupffer cells with gadolinium chloride (GdCl3) prevented the development of ethanol-dependent pathology and decreased the production of radicals that appeared in the bile of intragastrically alcohol-fed rats. If the induction of CYP2E1 and subsequent formation of oxidant species by the enzyme is causative in the ethanol-dependent hepatic pathology, then protection by GdCl3 could be due an inhibition of CYP2E1 induction. In the current study, ethanol-administration for 4 wk produced marked steatosis, necrosis, and inflammation not seen in control rats. Immunochemically, CYP2E1 was induced 5- to 6-fold in microsomes from the ethanol-treated animals. Rates of p-nitrophenol and chlorzoxazone hydroxylation were elevated approximately 3-fold, consistent with CYP2E1 induction. When GdCl3 was administered with ethanol, there was a decrease of approximately 80% in Kupffer cell receptor expression, and there was a significant decrease in hepatic pathology, which confirms previous studies. However, in the ethanol and GdCl3-treated animals, there was no significant decrease in the induction of CYP2E1. CYP2E1 was elevated approximately 5-fold, as estimated by immunoblot analysis, and rates of p-nitrophenol and chlorzoxazone hydroxylation were elevated 3- to 4-fold in ethanol + GdCl3-treated rats. Thus, these results clearly dissociate the induction of CYP2E1 by intragastric infusion of ethanol from the generation of early alcohol-induced liver disease. It is concluded that Kupffer cells rather than CYP2E1 play the major role in the initiation of hepatocyte damage caused by alcohol.
Mol Pharmacol 1997 Jun
PMID:Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1. 918 60

The human Dubin-Johnson syndrome is an autosomal recessive liver disease characterized by a chronic conjugated hyperbilirubinemia. Patients have impaired hepatobiliary transport of many endogenous and xenobiotic compounds. A similar disease phenotype has been described for a naturally occurring mutant Wistar rat strain, the TR- rat, which is defective in the, functionally defined, canalicular multispecific organic anion transporter (cMOAT). The complementary DNA encoding this protein has been cloned from rat and recently from human liver. cMOAT is a new member of the ATP-binding cassette transporter family, and homologous to the multidrug resistance-associated protein 1. A mutation in the cMOAT gene is responsible for the phenotype observed in TR- rats. This information should soon lead tc a complete genetic characterization of the human Dubin-Johnson syndrome.
J Mol Med (Berl) 1997 Jun
PMID:The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man. 923 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>