Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro metabolic activation of flutamide, a nitroaromatic antiandrogen which produces hepatitis in a few recipients, was first studied with male rat liver microsomes. There was no electron spin resonance evidence for the reduction of flutamide by reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase into a nitro anion free radical. In contrast, flutamide was oxidatively transformed by cytochrome P-450 into reactive metabolite(s) that covalently bound to microsomal proteins. Covalent binding required oxygen and NADPH, and was decreased by the nucleophile glutathione and by the cytochrome P-450 inhibitors SKF 525-A, piperonyl butoxide and troleandomycin (an inhibitor of the cytochrome P-450 3A subfamily). Covalent binding was increased markedly by pretreatment with dexamethasone (an inducer of the cytochrome P-450 3A subfamily) and moderately by pretreatment with beta-naphthoflavone (an inducer of the 1A family). Covalent binding was immunoinhibited markedly by anticytochrome P-450 3A immunoglobulin G and moderately by anticytochrome P-450 1A immunoglobulin G. Covalent binding was much lower with liver microsomes from female rats (not expressing P-450 3A2). Covalent binding of flutamide also occurred with human liver microsomes (where it was inhibited by troleandomycin), and with yeast microsomes expressing human liver cytochromes P-450 1A1, 1A2 or 3A4. We concluded that flutamide was oxidatively transformed into chemically reactive metabolite(s) by rat and human cytochromes P-450, including forms belonging to the 3A and 1A subfamilies.
 ...
PMID:Metabolic activation of the nitroaromatic antiandrogen flutamide by rat and human cytochromes P-450, including forms belonging to the 3A and 1A subfamilies. 838 41

The hepatocyte-specific paramagnetic magnetic resonance (MR) contrast agents manganese-DPDP [N,N'-dipyridoxylethylenediamine-N,N'-diacetate 5,5'bis-(phosphate)] and gadobenate dimeglumine were used for diagnosing chemically induced hepatitis in rats. Ex vivo liver tissue relaxation times and in vivo MR image signal-to-noise ratios were compared before and after contrast agent administration. Ex vivo relaxometry and in vivo MR imaging showed that Mn-DPDP enhanced normal and diseased livers to the same degree at all time points from 5 to 120 minutes. Gadobenate dimeglumine showed reduced T1 and T2 enhancements in hepatitis relative to those of normal liver, in the early phase (5-30 minutes). However, these effects are offsetting, and as a result, MR imaging failed to allow distinction of diseased from normal livers. This surprising result observed in vivo was in fact predicted by applying the Bloch equation to our ex vivo data. Our results show that detection and quantitation of hepatitis with MR imaging enhanced with paramagnetic cell-specific contrast agents will be more difficult than anticipated.
 ...
PMID:Evaluation of hepatocyte-specific paramagnetic contrast media for MR imaging of hepatitis. 840 May 66

We describe the structures and catalytic properties of several naturally occurring self-cleaving RNA motifs that give 2', 3' cyclic phosphate products. The hammerhead and hairpin motifs are derived from plant pathogenic RNAs and the delta motif is part of the human hepatitis delta element. A fourth motif from Neurospora is less well characterized. By assembling the self-cleaving RNAs from more than one oligoribonucleotide, the cleavage reaction can be examined under a variety of conditions and catalytic turnover can be demonstrated. Mutagenesis and chemical methods to introduce modified nucleotides allowed the structural requirements to be deduced. The role of divalent cations in the catalytic mechanism is discussed.
 ...
PMID:Self-cleaving catalytic RNA. 842 71

We recently found that phosphatidyl-2',3'-dideoxycytidine (phosphatidyl-ddC) had substantial anti-hepatitis B virus (HBV) activity in vitro compared to 2',3'-dideoxycytidine (ddC) (Hostetler et al. (1994) Antiviral Res. 24, 59-67). Upon administration of liposomal phosphatidyl-ddC to mice, a 40-fold higher drug area under curve was observed in the liver. To evaluate the possibility of using liver-targeted anti-HBV nucleosides to treat woodchuck hepatitis virus, we wanted to find the most potent and selective lipid conjugates. It has been shown that 2',3'-dideoxy-3'-thiacytidine as a racemic mixture of the cis-isomer (cis-(+/-)-BCH-189) has much greater activity against HBV viruses than ddC in vitro. Recently, it was shown that the (-)-beta-L-enantiomer (3TC) is more active and less toxic than the (+)-beta-D-form ((+)-BCH-189). To determine whether phospholipid conjugates of 3TC retain antiviral activity in 2.2.15 cells as demonstrated previously with ddC, we synthesized the 1,2-dipalmitoyl-sn-glycerol-3-phosphate conjugates of (+/-)-BCH-189 and 3TC and assessed their anti-HBV and anti-HIV activities, in vitro. Phosphatidyl-3TC and phosphatidyl-BCH-189 had antiviral activity comparable to the respective free drugs in 2.2.15 cells which chronically produce HBV. In HIV-1-infected human peripheral blood mononuclear cells and HT4-6C cells, phosphatidyl-3TC and phosphatidyl-(+/-)-BCH-189 exhibited significantly lower activity than the corresponding free nucleosides. In view of the documented ability of phosphatidyl-ddC to target drug to the liver, it seems reasonable to expect that phosphatidyl-3TC or phosphatidyl-(+/-)-BCH-189 could be employed to provide greatly enhanced hepatic antiviral activity in HBV infection in vivo.
 ...
PMID:Phosphatidyl-2',3'-dideoxy-3'-thiacytidine: synthesis and antiviral activity in hepatitis B-and HIV-1-infected cells. 858 65

A non-Watson-Crick G.G interaction within the core region of the hepatitis delta virus (HDV) antigenomic ribozyme is required for optimal rates of self-cleavage activity. Base substitutions for either one or both G's revealed that full activity was obtained only when both G's were replaced with A's. At those positions, substitutions that generate potential Watson-Crick, G.U, heteropurine, or homopyrimidine combinations resulted in dramatically lower cleavage activity. A homopurine symmetric base pair, of the same type identified in the high-affinity binding site of the HIV RRE, is most consistent with this data. Additional features shared between the antigenomic ribozyme and the Rev binding site in the vicinity of the homopurine pairs suggest some structural similarity for this region of the two RNAs and a possible motif associated with this homopurine interaction. Evidence for a homopurine pair at the equivalent position in a modified form of the HDV genomic ribozyme was also found. With the postulated symmetric pairing scheme, large distortions in the nucleotide conformation, the sugar-phosphate backbone, or both would be necessary to accommodate this interaction at the end of a helix; we hypothesize that this distortion is critical to the structure of the active site of the ribozyme and it is stabilized by the homopurine base pair.
 ...
PMID:Optimal self-cleavage activity of the hepatitis delta virus RNA is dependent on a homopurine base pair in the ribozyme core. 859 61

Self-cleaving sequences or ribozymes from the hepatitis delta virus (HDV) genomic RNA and its complement form similar secondary structures that suggest a core region and potential active site composed of "single-stranded" sequences. However, there is little data on tertiary interactions in these ribozymes, therefore structural features were investigated using cross-linking and hydroxyl radical cleavage. Cross-links in cis and trans forms of the antigenomic RNA were generated using the photoactivatable azidophenacyl group tethered to the cleavage site phosphate. Specific cross-links formed to J4/2, and to the 3' sides of P3 and L3. Different sites were cross-linked in low salt or monovalent cations versus divalent cations, suggesting a metal ion-dependent conformational change near the cleavage site. The solvent-inaccessible regions of both the genomic and antigenomic ribozymes were revealed by cleavage in Fe(II)-EDTA. In Mg2+, backbone segments most strongly protected from solvent-based hydroxyl radicals were mapped to J4/2 and parts of L3. Similar patterns of protection were seen in trans-acting ribozymes bound to a product oligonucleotide. These data provide evidence for a common tertiary structure for the HDV ribozymes. They would be consistent with a model in which the end of P1, including the cleavage site phosphate and the nucleotide 5' to the cleavage site, is positioned in an active site pocket or cleft formed by the three single-stranded regions, L3, J4/2, and J1/4.
 ...
PMID:Hepatitis delta virus ribozymes fold to generate a solvent-inaccessible core with essential nucleotides near the cleavage site phosphate. 878 96

The structure of an RNA hairpin containing a seven-nucleotide loop that is present in the self-cleaving sequence of hepatitis delta virus antigenomic RNA was determined by high resolution NMR spectroscopy. The loop, which is composed of only one purine and six pyrimidines, has a suprisingly stable structure, mainly supported by sugar hydroxyl hydrogen bonds and base-base and base-phosphate stacking interactions. Compared with the structurally well-determined, seven-membered anticodon loop in tRNA, the sharp turn which affects the required 180 degrees change in direction of the sugar-phosphate backbone in the loop is shifted one nucleotide in the 3' direction. This change in direction can be characterized as a reversed U-turn. It is expected that the reversed U-turn may be found frequently in other molecules as well. There is evidence for a new non-Watson-Crick UC base pair formed between the first and the last residue in the loop, while most of the other bases in the loop are pointing outwards making them accessible to solvent. From chemical modification, mutational and photocrosslinking studies, a similar picture develops for the structure of the hairpin in the active ribozyme indicating that the loop structure in the isolated hairpin and in the ribozyme is very similar.
 ...
PMID:The structure of the isolated, central hairpin of the HDV antigenomic ribozyme: novel structural features and similarity of the loop in the ribozyme and free in solution. 921 9

This report shows that loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) locus occurred in 5/8 (63%) dysplastic liver lesions and 11/18 (61%) hepatocellular carcinomas (HCCs) associated with the high risk factors of hepatitis virus infection and liver cirrhosis. Mutations in the remaining allele were detected in 6/11 (55%) HCCs, including deletions in a polydeoxyguanosine region known to be a target of microsatellite instability. M6P/IGF2R allele loss was also found in cirrhotic tissue of clonal origin adjacent to these dysplastic lesions and HCCs, demonstrating that M6P/IGF2R inactivation occurs early in liver carcinogenesis. In conclusion, HCCs frequently develop from clonal expansions of phenotypically normal, M6P/IGF2R-mutated hepatocytes, providing further support for the idea that M6P/IGF2R functions as a liver tumor-suppressor gene.
 ...
PMID:Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. 929 14

Crystallization of RNA molecules other than simple oligonucleotide duplexes remains a challenging step in structure determination by X-ray crystallography. Subjecting biochemically, covalently and conformationally homogeneous target molecules to an exhaustive array of crystallization conditions is often insufficient to yield crystals large enough for X-ray data collection. Even when large RNA crystals are obtained, they often do not diffract X-rays to resolutions that would lead to biochemically informative structures. We reasoned that a well-folded RNA molecule would typically present a largely undifferentiated molecular surface dominated by the phosphate backbone. During crystal nucleation and growth, this might result in neighboring molecules packing subtly out of register, leading to premature crystal growth cessation and disorder. To overcome this problem, we have developed a crystallization module consisting of a normally intramolecular RNA-RNA interaction that is recruited to make an intermolecular crystal contact. The target RNA molecule is engineered to contain this module at sites that do not affect biochemical activity. The presence of the crystallization module appears to drive crystal growth, in the course of which other, non-designed contacts are made. We have employed the GAAA tetraloop/tetraloop receptor interaction successfully to crystallize numerous group II intron domain 5-domain 6, and hepatitis delta virus (HDV) ribozyme RNA constructs. The use of the module allows facile growth of large crystals, making it practical to screen a large number of crystal forms for favorable diffraction properties. The method has led to group II intron domain crystals that diffract X-radiation to 3.5 A resolution.
 ...
PMID:A general module for RNA crystallization. 964 82

Determining the possible association of viral hepatitis infection and degree of pruritus is the primary concern of this study. Ninety-six adequately dialyzed CAPD patients (47 male and 49 female) and 526 normal controls (266 male and 260 female) were enrolled. Blood hemoglobin, ferritin, electrolytes, calcium, phosphate, albumin, urea, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and bilirubin were analyzed by routine methods. Serum HBsAg was examined, using a radioimmunoassay method and the anti-HCV, an enzyme immunoassay method. All cases were interviewed with a standardized questionnaire. The highest possible pruritus score (PS) was 22. The prevalences of HBsAg(+) and anti-HCV(+) were 14.6% and 17.7%, respectively. The mean PS in all 96 CAPD patients was 11.6 (range 7-22). The mean PS were 11.8 +/- 0.6 and 12.5 +/- 1.0 for patients infected with HBV and HCV, respectively. Both were significantly higher than that (10 +/- 0.9) of patients without hepatitis infection. AST and ALT were significantly higher in patients infected with viral hepatitis than those without. The other biochemical parameters were not significant. Thirty-seven (38.5%) of our 96 patients had mild pruritus (PS < or = 7) and 11 (15.9%) had severe pruritus (PS > or = 15). Of the 83.9% (26/31) patients with viral hepatitis, the grades of skin itching were moderate to severe; whereas those of the patients without viral hepatitis, 53.6% (37/69) belonged to the group of moderate to severe pruritus (p = 0.003, chi 2 test with Yates' correction). The authors recommended screening of viral hepatitis infection to be undertaken for uremic patients with unexplained skin itching.
 ...
PMID:Viral hepatitis infection should be considered for evaluating uremic pruritus in continuous ambulatory peritoneal dialysis patients. 968 Nov 57


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