Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolism of nitroglycerin (GTN) in the vascular smooth muscle is required for the drug to be effective in the treatment of angina pectoris and congestive heart failure. The usefulness of GTN is limited by the development of tolerance to the drug. The metabolism of GTN was studied in its target tissue, vascular smooth muscle. Inorganic nitrite was produced by cultured smooth muscle cells when GTN was added to the culture dish. Nitrite production increased with increasing GTN concentration and with incubation time. The enzymatic nature of GTN metabolism to nitrite was assessed by enzyme inhibition studies. Indocyanine green, a non-substrate inhibitor of glutathione S-transferase, inhibited GTN metabolism by smooth muscle cells. Cellular glutathione is also involved in GTN metabolism by the smooth muscle cell. Pretreatment with phorone, a glutathione S-transferase substrate, depleted cellular glutathione and decreased nitrite production from GTN. Pretreatment with buthionine sulfoximine, inhibitor of gamma-glutamylcysteine synthetase, decreased intracellular glutathione and caused decreased GTN metabolism in smooth muscle cells. Removal of cysteine from the smooth muscle cell incubation medium in combination with buthionine sulfoximine pretreatment decreased GTN metabolism to a lower level than buthionine sulfoximine pretreatment alone. This study shows that glutathione S-transferase and glutathione are involved in GTN metabolism by cultured smooth muscle cells.
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PMID:Metabolism of nitroglycerin by smooth muscle cells. Involvement of glutathione and glutathione S-transferase. 154 Feb 13

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
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PMID:Mechanisms of action of nitrates. 787 67

Nitroglycerin (GTN) has been used as the drug of choice in the treatment of angina pectoris. It has been shown that some glutathione S-transferases (GSTs) catalyze the metabolic conversion from GTN to glyceryl dinitrates (GDNs). In this study, we examined the substrate specificity of GSTs for GTN. Alpha and mu GSTs were isolated from porcine liver and intestinal mucosa by means of CM-cellulose and glutathione-affinity column chromatography. Mu GSTs degraded GTN time-dependently and formed 1,3-GDN in preference to 1,2-GDN as a ratio (1,2-GDN/ 1,3-GDN) of 0.61, whereas alpha GSTs formed twice as much 1,2-GDN as 1,3-GDN. These results showed that two GST families participate in the metabolic conversion of GTN at different hydrolyzing portions of the nitrogroups.
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PMID:Variable glyceryl dinitrate formation as a function of glutathione S-transferase. 887 25

Although glyceryl trinitrate (GTN) has been used in the treatment of angina for many years, details of its conversion to the proximal activator (presumed to be NO or an NO congener) of soluble guanylyl cyclase (sGC) are still unclear. We reported previously that purified microsomal glutathione transferase 1 (MGST1) mediates the denitration of GTN. In the current study, we investigated in intact cells whether this enzyme also converts GTN to species that activate sGC (mechanism-based biotransformation). We utilized LLC-PK1 cells, a cell line with an intact NO/sGC/cGMP system, and generated a stable cell line that overexpressed MGST1. MGST1 in the stably transfected cells was localized to the endoplasmic reticulum, and microsomes from these cells exhibited markedly increased GST activity. Although incubation of these cells with GTN resulted in a 3-4-fold increase in GTN biotransformation, attributed primarily to an increase in formation of the 1,3-glyceryl dinitrate metabolite, GTN-induced cGMP accumulation in cells overexpressing MGST1 was not different than that observed in wild type cells or in cells stably transfected with empty vector. To determine whether overexpression of NADPH cytochrome P450 reductase might act in concert with MGST1 to generate activators of sGC, we assessed GTN-induced cGMP accumulation in MGST1-overexpressing cells that had been transiently transfected with CPR. In this case, GTN-induced cGMP accumulation was also not different than that observed in wild type cells. We conclude that although MGST1 mediates the biotransformation of GTN in intact cells, this biotransformation does not contribute to the formation of activators of sGC.
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PMID:Role of microsomal glutathione transferase 1 in the mechanism-based biotransformation of glyceryl trinitrate in LLC-PK1 cells. 1942 24