Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A substantial part of the interindividual variability in response to drugs and xenobiotics is related to genetically-determined impairment in drug metabolism. Several drug-metabolising enzymes are polymorphic in humans and often polymorphisms are strongly related to altered drug biodisposition and to the risk of developing adverse effects. Drugs used in general anaesthesia undergo polymorphic metabolism. Among these, halothane is metabolized by cytochrome P450 (CYP) 2E1 and, to a lesser extent, by CYP3A4 and CYP2A6. CYP2E1 also plays a key role in the metabolism of isoflurane, sevoflurane, enflurane and desflurane. CYP2B6, CYP3A4 and CYP2C9 play a relevant role in the metabolism of ketamine. The enzymes involved in the metabolism of thiopental and etomidate remains to be elucidated. Propofol is metabolized mainly by glucuronidation by uridine diphosphate-glucuronosyltransferases (UGTs) and by hydroxylation by CYP2B6 and CYP2C enzymes. The enzymes SULT1A1 and NQO1 participate in later steps in propofol metabolism. All the above-mentioned anaesthetic-metabolising enzymes are polymorphic in man. The present review analyzes the importance of enzymes in the metabolism of anaesthetics and common polymorphisms related to the biotransformation of general anaesthetics and it raises hypotheses on genetic and non-genetics factors related to altered response to anaesthetics that require further investigation. Based on functional relevance and allele frequencies, we identify the most promising targets for the clinical use of pharmacogenomic techniques in anaesthesia to prevent altered pharmacokinetics or adverse drug effects.
 ...
PMID:Polymorphic drug metabolism in anaesthesia. 1944 86

In recent years, exceptional progress has been observed in pharmacogenetics, i.e. investigations of inherited conditioning of the organism's response to drugs or xenobiotics. On the other hand, modern molecular biology techniques have been implemented, making it possible to perform studies determining the involvement of genetic factors in differing responses to agents employed in general anaesthesia. Unexpected and incorrect response of the organism to the administration of specific anaesthetics is most commonly associated with a genetic defect of the metabolic pathway of a given agent or its receptor. The majority of agents used in anaesthesia are metabolised in the liver by the cytochrome P450 superfamily enzymes (CYPs) and phase II drug-metabolising enzymes: glutathione S-transferases (GSTs), sulphotransferases (SULTs), UDP-glucuronosyltransferases (UGTs) and NAD(P)H:quinone oxidoreductase (NQO1). Propofol is presently widely used for gastrointestinal (GI) and several other procedures. Among genes associated with metabolism of the most commonly applied anaesthetics such as propofol and sevoflurane, the following ones can be mentioned: CYP2E1, CYP2B6, CYP2C9, GSTP1, UGT1A9, SULT1A1 and NQO1. Moreover, the basic mechanism of propofol action involves its interaction with an ionotropic receptor GABAA inhibiting transfer of nerve impulses. Molecular studies have shown that polymorphic changes in GABRG2 receptor gene turn out to be important in the propofol anaesthesia. Planning of optimal anaesthesia can be considerably assisted by the determination of genetic factors of prognostic value taking advantage of genotyping and making it possible to select anaesthetics and reduce risk of side effects as well as undesirable actions.
 ...
PMID:The impact of genetic factors on response to anaesthetics. 2364 Sep 47

To explore the effects of propofol post-conditioning (PPC) on hepatic ischaemia/reperfusion injury (HIRI) and the potential mechanisms that might be involved in the interaction of Brahma-related gene1(BRG1) and Nuclear-related factor 2(Nrf2). Patients were randomized into PPC(n = 16) and non-PPC(NPC)( n = 21) groups. Propofol(2 mg/kg) was infused within 10 min. of the onset of liver reperfusion during liver transplantation in the PPC group. Liver function tests, as well as Brg1, Nrf2, Heme oxygenase-1(HO-1) and NADPH:quinone oxidoreductase1(NQO1) expression levels were evaluated. CMV-Brg1 mice were designed to investigate the role of Brg1 overexpression during HIRI. Brg1 and Nrf2 siRNA were used to examine the relationship between Brg1 and Nrf2/HO-1 pathways in propofol-mediated effects in a human hepatocyte(L02) hypoxia/reoxygenation(H/R) model. In patients, PPC attenuated both donor liver pathological and function injury, and reducing oxidative stress markers, compared to the NPC group, 24 hrs after surgery. PPC increased liver Brg1, Nrf2, HO-1 and NQO1 expression. In mice, PPC reduced HIRI by decreasing liver oxidative stress and activating Nrf2/HO-1 pathway, accompanied by up-regulation of BRG1 expression. BRG1 overexpression activated Nrf2/HO-1 transcription in CMV-BRG1 mice during HIRI. In vitro, PPC significantly elevated expression of Nrf2, HO-1 and NQO1, resulting in a reduction of cell DCFH-DA and 8-isoprostane levels and decreased lactate dehydrogenase levels, leading to an overall increase in cell viability. Moreover, the protective effects of propofol were partially abrogated in Nrf2-knock-down or BRG1-knock-down hepatocytes. Nrf2-knock-down drastically reduced protein expression of HO-1 and NQO1, while Brg1-knock-down decreased HO-1 expression. Propofol post-conditioning alleviates HIRI through BRG1-mediated Nrf2/HO-1 transcriptional activation.
 ...
PMID:Propofol post-conditioning alleviates hepatic ischaemia reperfusion injury via BRG1-mediated Nrf2/HO-1 transcriptional activation in human and mice. 2874 8