Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have analysed the dynamics of HBV variants related to Lamivudine resistance in 22 chronically infected patients during and after the end of Lamivudine therapy. Thirteen patients had a confirmed methionine mutation in the YMDD region of the reverse transcriptase domain determined by sequence analysis. They responded to therapy having a mean reduction of HBV DNA of 4.55 log (range 2.93-8.91). Nine patients partly responded to therapy, with a small decline of HBV DNA (mean reduction of 3.39 log, range 1.72-5.12) and no indication for an YMDD variant. Samples were re-analysed with a HBV Drug Resistance Line Probe assay (InnoLipa HBV-DR), which detected as low as 10% of a variant HBV population. With this assay, changes in the YMDD region were detected with a mean of 2 weeks (range -8 to 10) earlier than by an increase of HBV DNA levels. Increase of ALT was observed with a mean of 31 weeks (range 29-51) later than the methionine changes in the YMDD motif. Indications for a methionine into valine change could be determined in only one of the partial responders. An unexpected observation was the predominant presence of variant virus populations after end of therapy. In ten patients, we detected the wild type virus with a mean of 14 weeks after end of therapy (range 1-42 weeks). In three patients, no variant virus population could be detected at 25, 36 and 37 weeks, respectively, after cessation of treatment. This observation is important for the inclusion of the so-called naive patients in clinical trials.
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PMID:The dynamics of mutations in the YMDD motif of the hepatitis B virus polymerase gene during and after lamivudine treatment as determined by reverse hybridisation. 1212 23

Better understanding of hepatitis B virus (HBV) replication, natural history and the immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action are the basis for better therapeutic strategies against chronic hepatitis B. Among currently available drugs, interferon-alpha and thymosin-alpha1 have only modest efficacy (approximately 40% vs 9-20% in controls). In the past decade, lamivudine has dominated in the treatment of chronic HBV infection because it is easy to use, safe, and is effective in terms of hepatitis B e antigen and/or HBV-DNA loss, ALT normalization, and improvement in histology. The response rate increases with increasing pretherapy alanine aminotransferase (ALT) levels, suggesting that patients with stronger endogenous immune response against HBV have a better response to direct antiviral agents. Lamivudine is also beneficial in decompensated cirrhotics with HBV replication. Hepatitic flares may occur after stopping lamivudine therapy in nonresponders and also in responders. Therefore, prolonged therapy is usually required. However, tyrosine-methionine-aspartate-aspartate (YMDD) mutations conferring resistance to lamivudine start to emerge after 6-9 months of therapy, and hepatitis flare, even decompensation, may develop after viral breakthrough. Thus the benefits of long-term lamivudine therapy must be balanced against the concern about YMDD mutations and the durability of treatment response. Adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/ nucleotide analogues have shown encouraging results and some agents appear effective in patients with YMDD mutants. Further development of new drugs and new strategies may help to improve treatment in the new century.
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PMID:Therapy of chronic hepatitis B: current challenges and opportunities. 1243 Dec

Lamivudine is a nuleoside analog with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase confering resistance to lamivudine may emerge after 6-9 months therapy with an incidence of 38% and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV-DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occurred as the results of cytotoxic T lymphocyte mediated immune response directed against YMDD mutant. Although viral clearance with or without emergence of distinct lamivudine resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those occur during the natural course of wild type HBV chronic infection. The current practice of continuing lamivudine therapy, therefore, requires careful evaluation. Alternatives include interferon therapy but this seems ineffective. Adefovir dipivoxil and entecavir may effectively suppress the YMDD mutant but these treatments have not yet been available for use. Recent studies have shown no benefit to continuing lamivudine therapy in patients with YMDD mutantions. Before a rescue drug becomes available, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity to increase efficacy and to shorten the duration of lamivudine therapy to avoid the emergence of YMDD mutations.
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PMID:Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. 1247 59

The emergence of drug-resistant virus in hepatitis B virus (HBV) patients treated with lamivudine is well documented. In this study, we determined the mutations occurring in the tyrosine-methionine-aspartate-aspartate (YMDD) amino acid motif of the HBV DNA polymerase gene, as well as upstream and downstream of this region, in patients with breakthrough virus during lamivudine therapy. Thirty-one Turkish patients (20 patients HBeAg positive, 11 patients HBeAg negative and anti-HBe positive) with chronic HBV infection who completed at least 104 weeks of lamivudine treatment were investigated. All patients received lamivudine, (150 mg/day), for 104 weeks, with or without 4 months of interferon (IFN) combination. HBV-specific sequences were amplified by polymerase chain reaction (PCR) from sera of patients with breakthrough virus, and the PCR products were directly analysed by sequencing. Breakthrough virus was detected in seven of the 31 patients (22.6%) between 9 and 18 months of therapy. Of the seven patients, six were HBeAg positive at baseline, and four had a double mutation consisting of rtM204V and rtL180M, while two had an rtM204I change. In one patient, two base substitutions at rt204 (ATG --> AGT; T to G and G to T) lead to a methionine to serine change (YMDD --> YSDD). This novel DNA pol mutation was detected at month 18 of lamivudine treatment. In addition, this new variant had the rtL180M mutation and a 12 base pair deletion in the pre-S1 region between nucleotides 43-54. The YSDD mutation was still present 6 months after lamivudine discontinuation. In vitro transfection studies also confirmed that the YSDD strain is resistant to lamivudine. In conclusion, the results indicate that, in addition to a Met --> Val and Met --> Ile change in YMDD, a Met --> Ser change at rt204 (YMDD --> YSDD) associated with the rtL180M change can also emerge during lamivudine treatment, which confers lamivudine resistance in vivo and in vitro, leading to virological breakthrough and ALT increases.
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PMID:YSDD: a novel mutation in HBV DNA polymerase confers clinical resistance to lamivudine. 1282 91

We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor alpha (PPARalpha) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPARalpha(-/-) mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPARalpha(-/-) mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPARalpha agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal beta-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPARalpha(-/-) mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPARalpha activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis.
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PMID:Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. 1282 80

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are common liver diseases in the United States. ASH and NASH occur more frequently in women than in men, and liver injury is also more severe in women. The role of estrogens in ASH has been well established, but their role in NASH has received relatively little study. The purpose of this study was to evaluate the effect of estrogens in methionine-choline deficient diet (MCDD)-induced steatohepatitis in mice. The degree of steatohepatitis was evaluated in males and in intact and ovariectomized females that were fed MCDD for 4 weeks, and in females that were fed MCDD containing tamoxifen. Hematoxylin and eosin-stained sections of livers showed marked steatohepatitis in all experimental groups. Compared to the control group, markers of hepatocyte injury such as aspartate transaminase (AST), alanine transaminase (ALT), and liver triglyceride levels increased significantly in males and in intact and ovariectomized female mice that were fed MCDD. Also, it was interesting that levels of AST and ALT increased much more in the MCDD + tamoxifen group than in the MCDD group. In female mice fed MCDD, hepatocyte proliferative and apoptotic indices increased slightly compared to mice that were fed a normal diet. Based on these results, it can be concluded that MCDD-induced steatohepatitis is comparable in male and female mice, and that ovariectomy or antiestrogen treatment had no protective effect in MCDD-induced steatohepatitis.
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PMID:Sex differences in choline-deficient diet-induced steatohepatitis in mice. 1473 94

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.
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PMID:Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. 1504 74

Short term exposure of arsenic produces carbohydrate depletion and hypoglycemia. Dietary deficiency of methionine causes impaired biotransformation of arsenic which has been attributed to the pathogenesis of different diseases induced by arsenic. Accordingly, the effects of methionine supplementation on the altered glucose homeostasis induced by arsenic were studied. Arsenic (as sodium arsenite) treatment (i.p) of male Wistar rats (weighing 80-100 g) at a dose of 5.55 mg kg(-1) body weight (equivalent to 35% LD50) per day for a period of 21 days caused a significant diminution in blood glucose level and fall in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content of liver was elevated while that of kidney was decreased after arsenic treatment. Transaminase activities in liver and kidney were not significantly altered except that glutamate-pyruvate transaminase activity of kidney decreased significantly after arsenic treatment. Methionine supplementation reversed the above changes except decreased liver glycogen due to arsenic treatment. It may be suggested that hypoglycemia with associated decreased glycolytic activity induced by arsenic treatment at the present dose and duration can be partially counteracted by dietary methionine supplementation.
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PMID:Protective effect of methionine supplementation on arsenic-induced alteration of glucose homeostasis. 1504 19

Reactivation of hepatitis B virus (HBV) after cytotoxic chemotherapy is a serious problem, and it occurred to 41% of breast cancer patients carrying HBV. Previous studies have demonstrated that lamivudine was effective for HBV flare-up during cytotoxic chemotherapy. We aimed to monitor the HBV status of breast cancer patients undergoing chemotherapy with preemptive lamivudine over time. Six breast cancer patients carrying hepatitis B surface antigen (HBsAg) were monitored during chemotherapy, five in the adjuvant setting and one with metastatic disease. Preemptive lamivudine was given throughout the chemotherapy course. HBsAg, HBV envelope antigen (HBeAg), anti-HBV envelope antibody (HBe Ab), serial serum alanine transaminase (ALT), quantitative HBV viral DNA analysis, and HBV DNA precore promoter and precore sequence were monitored. One patient carried wild type and the other five precore mutant strain of HBV by examination of HBV sequence in precore promoter and precore region. No evident HBV reactivation developed, and all patients tolerated lamivudine well. During the 6-to-8-month follow-up after cessation of cytotoxic therapy and withdrawal of lamivudine, serum ALT remained unchanged, although an increase of HBV DNA levels in four patients was found. No emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) lamivudine-selective resistant strain was observed in the six patients. Preemptive use of lamivudine can effectively prevent reactivation of HBV in breast cancer patients receiving postoperative adjuvant chemotherapy. Lamivudine can be discontinued safely without emergence of lamivudine-resistant HBV strain or rebound HBV flare-up. The candidate for the use of preemptive lamivudine in HBV carriers who need short-term chemotherapy remained to be investigated
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PMID:Preemptive use of lamivudine in breast cancer patients carrying hepatitis B virus undergoing cytotoxic chemotherapy: a longitudinal study. 1507 16

Administration of a methionine and choline deficient (MCD) diet to rodents causes progressive fibrosing steatohepatitis pathologically similar to human metabolic steatohepatitis. We have previously shown that the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, Wy-14,643, prevented the development of MCD diet-induced steatohepatitis. We have now tested whether Wy-14,643 ameliorates established steatohepatitis and fibrosis. Male C57BL6 mice were fed the MCD diet for 51 days to induce severe steatohepatitis. They were then treated with Wy-14,643 together with the MCD diet for 5 or 12 days; positive controls continued on the MCD diet for 5 or 12 days. After 5 days of Wy-14,643 treatment, alanine aminotransferase (ALT) levels were significantly decreased, steatohepatitis less severe, and hepatic lipoperoxides significantly reduced. After 12 days, hepatic triglycerides were normalized and there was near resolution of histological changes. MCD dietary feeding was associated with increased expression of vascular cell adhesion molecule (VCAM)-1, and increased numbers of activated macrophages in the liver. Treatment with Wy-14,643 reduced VCAM-1 expression and macrophage numbers. MCD diet-fed mice developed hepatic fibrosis with increased hepatic collagen alpha1(I), tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, and matrix metalloproteinase (MMP)-13 mRNA levels. After treatment with Wy-14,643, expression of these genes was reduced in a manner that paralleled the reduction in activated hepatic stellate cells and near resolution of liver fibrosis. In conclusion, the present study shows that MCD diet-induced fibrosing steatohepatitis can be reversed by treatment with Wy-14,643. It is likely that activation of PPARalpha reverses fibrosis indirectly by reducing stimuli, such as lipid peroxides, and activation of cells responsible for promoting hepatic fibrosis.
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PMID:Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. 1512 57


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