Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung is a target organ for the toxicity of inhalated compounds. The respiratory tract is frequently exposed to elevated concentrations of these compounds and become the primary target site for toxicity. Occupational, accidental or prolonged exposure to a great variety of chemicals may result in acute or delayed injury to cells of the respiratory tract. Nevertheless, lung has a significant capability of biotransforming such compounds with the aim of reducing its potential toxicity. In some instances, the biotransformation of a given compound can result in the generation of more reactive, and frequently more toxic, metabolites. Indeed, lung tissue is known to activate pro-carcinogens (i.e. polycyclic aromatic hydrocarbons or N-nitrosamines) into more reactive intermediates that easily form DNA adducts. Lungs express several enzymes involved in the metabolising of xenobiotics. Among them, cytochrome P450 enzymes are major players in the oxidative metabolism as well metabolic bioactivation of many organic toxicants, including pro-carcinogens. Xenobiotic-metabolising P450 enzymes are expressed in bronchial and bronchiolar epithelium, Clara cells, type II pneumocytes, and alveolar macrophages Individual CYP isoforms have different patterns of localisation within pulmonary tissue. With the aid of sensitive techniques (i.e. reverse transcriptase-polymerase chain reaction, RT-PCR) it has become possible to detect CYP1A1, CYP1B1, CYP2A6, CYP2B6, CYP2E1 and CYP3A5 mRNAs in lung cells. Less conclusive results have been obtained concerning CYP2Cs, CYP2D6 and CYP3A4. CYP3A5 protein appears to be widely present in all lung samples and is localised in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated epithelium and in type I and type II alveolar epithelium. Lung cells also express Phase II enzymes such as epoxide hydrolase, UGT1A (glucuronyl transferase) and GST-P1 (glutathione S-transferase), which largely act as detoxifying enzymes. A key question concerning organ-specific chemical toxicity is whether the actual target has the capacity to activate (or efficiently inactivate) chemicals. Results of several studies indicate that the different xenobiotic-metabolising CYPs, present in the human lung and lung-derived cell lines, likely contribute to in situ activation of pulmonary toxins, among them, pro-carcinogens. Some CYPs, in particular CYP1A, are polymorphic and inducible. Interindividual differences in the expression of these CYPs may explain the different risk of developing lung toxicity (possibly cancer), by agents that require metabolic activation. Few cell lines, principally A549, have been used with variable success as an experimental model for investigating the mechanisms of toxicity. Although RT-PCR analysis has evidenced the presence of the major human pulmonary CYP mRNAs, the measurable P450 specific activities are, however, far below those present in human lungs. Detection of the toxicity elicited by reactive metabolites requires the use of metabolically competent cells; consequently, better performing cells are needed to ensure realistic in vitro prediction of toxicity. Genetic manipulation of lung-derived cells allowing them to re-express key biotransformation enzymes appear to be a promising strategy to improve their functionality and metabolic performance.
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PMID:Metabolism and bioactivation of toxicants in the lung. The in vitro cellular approach. 1609 27

To investigate the impacts of marine pollution on aquatic organisms, we tested the intertidal copepod Tigriopus japonicus as a model species. To analyze the copepods' responses to endocrine-disrupting chemicals (EDCs), we exposed them to two different chemicals: 4,4'-octylphenol (4,4'-OP, 12.5-100 microg/L for 2 h) and polychlorinated biphenyl (PCB, 6.25-25 microg/L for two days). 4,4'-OP was toxic, although exposure time was limited to 2h. After extracting total RNA from the exposed T. japonicus, we performed reverse transcriptase-polymerase chain reaction (RT-PCR) to determine gene expression patterns following chemical exposure. To analyze the gene expression of T. japonicus, we used glutathione S-transferase with GAPDH as an internal control. Of the genes tested using EDC-exposed samples, 4,4'-OP induced upregulation of the glutathione S-transferase (GST) gene, while PCB caused downregulation of the GST gene. These results suggest that the two EDCs act in different manners in T. japonicus.
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PMID:Cloning and characterization of glutathione S-transferase gene in the intertidal copepod Tigriopus japonicus and its expression after exposure to endocrine-disrupting chemicals. 1672 91

There is substantial overlap in retinol and alcohol metabolism. Mice that lack retinoic acid (RA) receptor retinoid X receptor alpha (RXRalpha) expression in the liver are more susceptible to alcoholic liver disease. To investigate the interaction between RXRalpha and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXRalpha-deficient [RXRalpha knockout (KO)] mice. Hepatocyte RXRalpha deficiency resulted in a significant increase in hepatic alcohol dehydrogenase (ADH) activity, ADH1 protein, but not Adh1 mRNA. Polysomal distribution analysis indicated that more polysome-associated Adh1 mRNA was present in the mutant mouse livers, suggesting increased ADH1 protein synthesis in RXRalpha KO mice compared with wild-type mice. However, ADH2 and ADH3 enzyme activities were not affected by RXRalpha deficiency. Although ethanol clearance was increased, acetaldehyde elimination was reduced when RXRalpha was not expressed in the liver. Both mitochondrial aldehyde dehydrogenase (ALDH) 2 and cytosolic ALDH activities were reduced in the mutant mice compared with the wild type. Western blot analysis revealed that the levels of ALDH1A1 and ALDH1A2 were decreased in the mutant mice. Semiquantitative reverse transcriptase-polymerase chain reaction indicated that liver Aldh1a1 mRNA level was also reduced due to the lack of RXRalpha expression. Thus, RXRalpha differentially affects ADH and ALDH activity, leading to an increase in alcohol clearance, but a reduction in acetaldehyde elimination. In addition, CYP2E1 as well as mitochondrial and cytosolic glutathione S-transferase activities were significantly lower in RXRalpha KO mice than in wild-type mice. Our results reveal the central role of RXRalpha in ethanol metabolism.
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PMID:The role of retinoid X receptor alpha in regulating alcohol metabolism. 1682 25

The glutathione S-transferase Mu class (GSTM) genes encode phase II metabolism enzymes that are involved in the detoxification of various carcinogens and drugs. Some genetic polymorphisms in GSTM genes are related to disease phenotypes and drug-metabolism differences in the population. Polymorphisms that alter gene-splicing patterns are functionally very important because they often lead to the insertion or deletion of many amino acids. To identify inter-individual differences in the splicing pattern of the GSTM4 gene, we used reverse transcriptase polymerase chain reaction (RT-PCR) to screen cDNA from 96 human liver samples. We discovered a novel splice variant of GSTM4 that resulted from tandem skipping of exons 4 and 5. This exon-skipping event is associated with a mutation at the splice acceptor site in intron 4.
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PMID:Screening for inter-individual splicing differences in human GSTM4 and the discovery of a single nucleotide substitution related to the tandem skipping of two exons. 1685 33

A cDNA encoding glutathione S-transferase (GST) of the fall webworm, Hyphantria cunea, was cloned by reverse transcriptase-polymerase chain reaction. The resulting clone (hcGST) was sequenced and deduced for amino acid sequence, which revealed 87, 59, and 42% identities to Sigma-class GSTs from Bombyx mori, Manduca sexta, and Blattella germanica respectively. A recombinant hcGST protein (rhcGST) was functionally overexpressed in Escherichia coli cells in a soluble form and purified to homogeneity. rhcGST retained more than 75% of its original GST activity after incubation at pHs 6 to 11. Incubation for 30 min at temperatures below 50 degrees C scarcely affected the activity. rhcGST was able to catalyze the reaction of glutathione with 1-chloro-2,4-dinitrobenzene, a universal substrate for GST, as well as with 4-hydroxynonenal, a product of lipid peroxidation. We also found that as compared to B. mori Sigma-class GST, rhcGST had a higher affinity for fenitrothion, an organophosphorus insecticide.
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PMID:Expression and characterization of a sigma-class glutathione S-transferase of the fall webworm, Hyphantria cunea. 1728 39

The renaturation success of an urban stream, formally used for discharge of treated sewage waters was investigated by active biomonitoring with Dreissena polymorpha based on molecular biomarkers and compared to a semi-natural stream and laboratory controls. Response to pollution charges were analyzed by reverse transcriptase-PCR of heat-shock protein (hsp70), P-glycoprotein (P-gp), catalase (CAT) and pi class glutathione S-transferase (piGST). Hsp70 transcription was similarly induced at both sites, indicating protein damage. At the semi-natural stream CAT and P-gp were induced, indicating oxidative stress and increased discharge of pollutants, which correlated to high amounts of aluminum at this site. piGST was induced at one sampling date at the renaturated stream only, but identification of the causing pollutant was not achieved. Results confirm regeneration of the formerly sewage polluted stream, because induction of the tested biomarkers was either at or below the levels of the semi-natural stream.
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PMID:Molecular biomarkers of Dreissena polymorpha for evaluation of renaturation success of a formerly sewage polluted stream. 1804 58

Acaricide-inducible differential gene expression was studied in larvae of Rhipicephalus (Boophilus) microplus using a microarray-based approach. The acaricides used were: coumaphos, permethrin, ivermectin, and amitraz. The microarrays contained over 13 000 probes, having been derived from a previously described R. microplus gene index (BmiGI Version 2; Wang et al., 2007). Relative quantitative reverse transcriptase-PCR, real time PCR, and serial analysis of gene expression data was used to verify microarray data. Among the differentially expressed genes with informative annotation were legumain, glutathione S-transferase, and a putative salivary gland-associated protein.
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PMID:Microarray analysis of acaricide-inducible gene expression in the southern cattle tick, Rhipicephalus (Boophilus) microplus. 1883 53

A cDNA encoding an omega-class glutathione S-transferase of the silkmoth, Bombyx mori (bmGSTO), was cloned by reverse transcriptase-polymerase chain reaction. The resulting clone was sequenced and deduced for amino acid sequence, which revealed 40, 40, and 39% identities to omega-class GSTs from human, pig, and mouse, respectively. A recombinant protein (rbmGSTO) was functionally overexpressed in Escherichia coli cells in a soluble form and purified to homogeneity. rbmGSTO was able to catalyze the biotranslation of glutathione with 1-chloro-2,4-dinitrobenzene, a model substrate for GST, as well as with 4-hydroxynonenal, a product of lipid peroxidation. This enzyme was shown to have high affinity for organophosphorus insecticide and was present abundantly in silkmoth strain exhibiting fenitrothion resistance. These results indicate that bmGSTO could be involved in the increase in level of insecticide resistance for lepidopteran insects.
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PMID:Biochemical properties of an omega-class glutathione S-transferase of the silkmoth, Bombyx mori. 1902 97

The Ty1 retrotransposon of Saccharomyces cerevisiae is comprised of structural and enzymatic proteins that are functionally similar to those of retroviruses. Despite overall sequence divergence, certain motifs are highly conserved. We have examined the Ty1 integrase (IN) zinc binding domain by mutating the definitive histidine and cysteine residues and thirteen residues in the intervening (X(32)) sequence between IN-H22 and IN-C55. Mutation of the zinc-coordinating histidine or cysteine residues reduced transposition by more than 4,000-fold and led to IN and reverse transcriptase (RT) instability as well as inefficient proteolytic processing. Alanine substitution of the hydrophobic residues I28, L32, I37 and V45 in the X(32) region reduced transposition 85- to 688-fold. Three of these residues, L32, I37, and V45, are highly conserved among retroviruses, although their effects on integration or viral infectivity have not been characterized. In contrast to the HHCC mutants, all the X(32) mutants exhibited stable IN and RT, and protein processing and cDNA production were unaffected. However, glutathione S-transferase pulldowns and intragenic complementation analysis of selected transposition-defective X(32) mutants revealed decreased IN-IN interactions. Furthermore, virus-like particles with in-L32A and in-V45A mutations did not exhibit substantial levels of concerted integration products in vitro. Our results suggest that the histidine/cysteine residues are important for steps in transposition prior to integration, while the hydrophobic residues function in IN multimerization.
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PMID:Functional analysis of N-terminal residues of ty1 integrase. 1957 Aug 57

AP-1-like transcription factors play crucial roles in oxidative stress responses in yeast and filamentous fungi. The deletion of an AP-1-like transcription factor gene, nap-1, in Neurospora crassa slightly increased its sensitivity to oxidative stressors, including menadione. Microarray and quantitative real-time reverse transcriptase-PCR analyses were employed to identify menadione-inducible genes (migs) and the roles of NAP-1 in their regulation. N. crassa migs include three putative glutathione S-transferase genes and two NADH:flavin oxidoreductase genes, orthologs of OYE2 and OYE3, both of which play roles in menadione tolerance in Saccharomyces cerevisiae. Menadione induced nuclear localization of NAP-1, and oxidative upregulation of many of migs were NAP-1 dependent. Genes for a thioredoxin, a glutathione reductase, and a glutathione peroxidase were slightly upregulated by the chemical only in the wild-type strain, suggesting that NAP-1 is involved in their oxidative induction and probably dose not contribute to high-level constitutive expressions of such genes.
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PMID:An AP-1-like transcription factor, NAP-1, regulates expression of the glutathione S-transferase and NADH:flavin oxidoreductase genes in Neurospora crassa. 2037 91


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