Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug-induced hepatitis is uncommon and generally unpredictable. Hepatotoxicity may be related to the drug itself, or to chemically reactive metabolites which can bind covalently to hepatic macromolecules and may lead to either idiosyncratic, toxic hepatitis or to immunoallergic hepatitis. There is now evidence indicating that genetic variations in systems of biotransformation or detoxication may modulate either the toxic or sensitizing effects of some drugs. Thus, the genetic deficiency in a particular hepatic cytochrome P 450 isozyme (CYP 2D6) is involved in per-hexiline liver injury. The deficiency in CYP 2C19 might also contribute to Atrium hepatotoxicity. Slow acetylation related to N-acetyltransferase 2 deficiency contributes to sulfonamide hepatitis. The genetic deficiency in glutathione synthetase may increase the susceptibility to several drugs including acetaminophen. A constitutional deficiency in another cell defense mechanism, still not characterized, seems to increase significantly the risk of hepatotoxicity with halothane, phenytoin, carbamazepine, phenobarbital, sulfamides and amineptine.
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PMID:Genetic predisposition to drug-induced hepatotoxicity. 920 5

The Colorado potato beetle, Leptinotarsa decemlineata (Say), is a major agricultural pest in the Central Sands region of Wisconsin. Imidacloprid, a neonicotinoid insecticide, has commonly been used for control of L. decemlineata since its registration in 1995. In the last 10 years, many field populations of L. decemlineata have begun to show increasing imidacloprid resistance. We studied resistance phenotype as a phenomenon that reduces neonicotinoid efficacy and has practical consequences for potato pest management. Although we have not observed complete field failure following the use of these products, multiple studies have demonstrated that the lethal concentration to kill 50% of the test organisms (LC50) in different field populations of L. decemlineata varies greatly which may suggest that resistance of L. decemlineata is heritable and involves genetic changes. An important challenge in understanding resistance is assessing the genetic mechanisms associated with resistance and classifying up-regulated genes that may be involved in combating an insecticide insult. In this study we uncovered trends in imidacloprid phenotypic response that have developed in the region by estimating the LC50 values among different field populations against a range of imidacloprid doses. The LC50 values collected in 2008-2011, and more recently in 2013 and 2014, show that some field locations remain susceptible to imidacloprid, while nearby fields (<100km) have developed high levels of resistance. We also sought to uncover potential mechanisms of resistance at each field location. We compiled a transcriptome for populations, characterized as phenotypically 'susceptible' and 'resistant', by isolating mRNA from adult beetles and analyzing gene expression level differences. Strong differences were observed in constituently up and down-regulated genes among different field populations. Most significantly, the up-regulation of 3 cytochrome p450s and a glutathione synthetase related protein in multiple resistant populations provide a mechanistic explanation of resistance evolution in L. decemlineata.
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PMID:Characterizing Molecular Mechanisms of Imidacloprid Resistance in Select Populations of Leptinotarsa decemlineata in the Central Sands Region of Wisconsin. 2682 61

The Colorado potato beetle, Leptinotarsa decemlineata (Say), is a major agricultural pest of potatoes in the Central Sands production region of Wisconsin. Previous studies have shown that populations of L. decemlineata have become resistant to many classes of insecticides, including the neonicotinoid insecticide, imidacloprid. Furthermore, L. decemlineata has multiple mechanisms of resistance to deal with a pesticide insult, including enhanced metabolic detoxification by cytochrome p450s and glutathione S-transferases. With recent advances in the transcriptomic analysis of imidacloprid susceptible and resistant L. decemlineata populations, it is possible to investigate the role of candidate genes involved in imidacloprid resistance. A recently annotated transcriptome analysis of L. decemlineata was obtained from select populations of L. decemlineata collected in the Central Sands potato production region, which revealed a subset of mRNA transcripts constitutively up-regulated in resistant populations. We hypothesize that a portion of the up-regulated transcripts encoding for genes within the resistant populations also encode for pesticide resistance and can be suppressed to re-establish a susceptible phenotype. In this study, a discrete set of three up-regulated targets were selected for RNA interference experiments using a resistant L. decemlineata population. Following the successful suppression of transcripts encoding for a cytochrome p450, a cuticular protein, and a glutathione synthetase protein in a select L. decemlineata population, we observed reductions in measured resistance to imidacloprid that strongly suggest these genes control essential steps in imidacloprid metabolism in these field populations.
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PMID:RNA interference of three up-regulated transcripts associated with insecticide resistance in an imidacloprid resistant population of Leptinotarsa decemlineata. 2804 28