Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zidovudine (azidothymidine (AZT)) inhibits human immunodeficiency virus replication, prolongs survival, and delays progression of acquired immune deficiency syndrome. We determined AZT-induced molecular and ultrastructural changes in the rat heart. Rats (3 per group) were given drinking water with or without AZT (0.2 to 1.0 mg/ml; 29 to 102 mg/kg/day). After 21, 35, or 49 days, hearts were glutaraldehyde-fixed by abdominal aortic perfusion, processed, and examined by transmission electron microscopy. In parallel, myocardial RNA was extracted from hearts (AZT dose: 1 mg/ml; 35 days) and subjected to Northern analysis using cDNA probes for: alpha c-actin, troponin C, mitochondrial creatine kinase and malate dehydrogenase, a portion of the mitochondrial genome containing cytochrome b coding region (pMM26), and glyceraldehyde-3-phosphate dehydrogenase. Results showed marked and widespread cardiac mitochondrial swelling with fractured and disrupted cristae after 35 days of 1 mg/ml AZT. After a 14-day recovery, these ultrastructural defects did not reverse. Changes were not present in myocardium after 21 days of AZT nor after 35 days of lower dose AZT (0.2 mg/ml). Mitochondrial cytochrome b mRNA expression was depressed in AZT-treated rat hearts (35 days; 1 mg/ml AZT). mRNAs encoding glyceraldehyde-3-phosphate dehydrogenase, alpha c-actin, troponin C, mitochondrial creatine kinase, malate dehydrogenase, and mitochondrial ribosomal RNAs remained unchanged. AZT disrupts cardiac mitochondrial ultrastructure and expression of mitochondrial cytochrome b mRNA in a dose- and time-dependent fashion. The mechanism of AZT cardiotoxicity may relate to inhibition of mitochondrial DNA replication (at the level of DNA polymerase gamma) as postulated by others.
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PMID:Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts. 171 47

Muscle biopsy specimens were obtained from 48 human immunodeficiency virus-infected patients suffering from various neuromuscular symptoms. Microscopic examination by conventional and electron microscopy revealed a characteristic structural myopathy associated with mitochondrial changes in 13 patients, all of whom had received long-term zidovudine therapy. The mean cumulative dose they had received (498 +/- 145 gm) was significantly higher than that of the other 14 zidovudine recipients of the study. They suffered from a progressive, usually painful, proximal myopathy with pronounced wasting, normal-to-moderately elevated creatine kinase levels, and a myopathic electromyographic pattern. The condition usually improved after withdrawal of the drug. Assay of mitochondrial enzymes, including succinate-cytochrome c reductase, cytochrome c oxidase, and citrate synthase, showed a decline in respiratory chain capacity. Southern blot analysis of mitochondrial DNA showed no abnormality. It is likely that mitochondrial dysfunction, probably resulting from drug-induced inhibition of the mitochondrial DNA polymerase, is implicated in the pathogenesis of this complication of zidovudine therapy.
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PMID:Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. 189 64

Bacteriophage XP-12-infected Xanthomonas oryzae have been found to be a source of a kinase preparation which converts m5dCMP to m5dCDP and then to m5dCTP using ATP as the phosphate donor. Optimal formation of the triphosphate required the presence of creatine phosphate and creatine kinase. In the presence of dGTP, dTTP and dATP, Escherichia coli DNA polymerase I and T4 DNA polymerase catalyzed the incorporation of m5dCTP into DNA just as efficiently as that of dCTP. Neither dTMP nor dCMP served as substrate for the m5dCMP monophosphate kinase. Analogous preparations from uninfected X. oryzae were unable to phosphorylate m5dCMP.
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PMID:A bacteriophage-induced 5-methyldeoxycytidine 5'-monophosphate kinase. 708 69

The aim of this review is to summarize the safety profile of the five approved oral nucleoside analogs used to treat chronic hepatitis B virus (HBV) infection, focusing on both the class adverse effects and those that have been reported with individual agents, as well as their safety in pregnancy. All nucleoside analogs have a "Black Box" warning because of their potential for inhibition of human DNA polymerase gamma involved in mitochondrial DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying clinical manifestations of mitochondrial toxicity (i.e., neuropathy, myopathy, lactic acidosis), but these side effects are rarely reported with the oral antiviral agents active against HBV. Adefovir and tenofovir are associated with a dose-dependent but usually reversible proximal renal tubular toxicity. For these reasons, patients receiving these agents should be monitored for renal toxicity and the dose modified for renal insufficiency. Prolonged use of tenofovir has also been reported to lead to reduced bone mineral density in patients with human immunodeficiency virus infection, but prospective studies in patients with HBV infection are lacking. Telbivudine treatment is associated with moderate serum creatine phosphokinase elevations in up to 12% of patients. There have been few prospective studies on the safety of nucleoside analogs during pregnancy. According to the Antiretroviral Pregnancy Registry, the incidence of birth defects associated with lamivudine and tenofovir use during pregnancy is not increased. Studies on the safety of long-term therapy with the nucleoside analogs, alone and in combination, are needed as are further studies of children, the elderly, pregnant women, and patients with renal insufficiency.
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PMID:Side effects of long-term oral antiviral therapy for hepatitis B. 1939 2

Oral nucleoside/nucleotide analogues (NAs) are the mainstay of therapy for patients with chronic hepatitis B and are generally well tolerated. Despite this, the safety profile of NAs is of paramount importance since the majority of patients will require long-term treatment. All NAs can potentially affect human DNA polymerase with decrease in mitochondrial DNA, leading to manifestations of mitochondrial toxicity. As a class effect, therefore, NAs can potentially cause extrahepatic conditions, such as myopathy, nephropathy, neuropathy, and lactic acidosis. Indeed, effects on muscles, including myopathy and creatine kinase elevations, have been described with clevudine and telbivudine use. Both adefovir and tenofovir are associated with dose-dependent nephropathy, predominantly affecting the proximal renal tubules. Neuropathy appears to be rare, and most commonly reported in patients receiving combination therapy with telbivudine and interferon. Increased risk of lactic acidosis has also been described for those with impaired liver and renal function taking entecavir. Loss of bone mineral density and hypophosphatemia have been described with the use of NAs, although the overwhelming studies have been with human immunodeficiency virus-infected patients. However, not all extrahepatic effects are detrimental. Recent evidence has suggested a potential renal beneficial effect with the use of telbivudine. The effect of NAs on pregnancy appears to be minimal for all NAs, with telbivudine and tenofovir having a more favorable category B rating. Ongoing pharmacovigilance is essential to identify new and monitor existing extrahepatic effects associated with NA use.
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PMID:Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis B treatment. 2437 62