1.0 2011-09-21 00:09:41 UTC 2024-11-29 22:25:18 UTC FDB022179 Indoxyl sulfate Indoxyl sulfate, also known as 3-indoxyl sulfate, is a member of the class of organic compounds known as arylsulfates. These are organic compounds containing a sulfate group that carries an aryl group through an ether group. Indoxyl sulfate is a metabolite of the common amino acid tryptophan and is derived through the consumption, digestion and microbial processing of protein-rich foods. Indoxyl sulfate is technically a bacterial co-metabolite, meaning that it is derived from both bacterial and host metabolism. Specifically, it is generated from dietary L-tryptophan which is converted to indole in the large intestine via tryptophanase-expressing gastrointestinal bacteria (PMID: 27102537). The resulting indole is converted to indoxyl in the liver via enzyme-mediated hydroxylation by the CYP450 enzyme CYP2E1 (PMID 11808865). Subsequently, indoxyl is converted into indoxyl sulfate by the SULT1A1 sulfotransferase enzyme in the liver (PMID: 12064372). Indoxyl sulfate has been identified as a uremic toxin according to the European Uremic Toxin Working Group (PMID: 22626821 ) and is classified as a protein-bound uremic solute. Indoxyl sulfate is known to bind to serum albumin (PMID: 22626821), to be transported by the OAT1 transporter (PMID: 34678967) and to be an agonist for the arylhydrocarbon receptor (AhR) (PMID: 32527975). High concentrations of indoxyl sulfate in whole blood or blood plasma are known to be associated with the development and progression of chronic kidney disease (CKD) as well as the development of cardiovascular disease (CVD) in humans and other mammals (PMID: 28754616). As a uremic toxin, indoxyl sulfate is known to stimulate glomerular sclerosis (PMID: 8035108), interstitial fibrosis (PMID: 33138205) and increase the rate of progression of renal failure. Indoxyl sulfate is a known tubular toxin (i.e., a renal tubule toxin) and directly induces apoptotic and necrotic cell death of tubular cells in the kidney (PMID: 33138205). Indoxyl sulfate upregulates signal transducers and activators of transcription 3 phosphorylation leading to increases in TGF-β1, monocyte chemotactic protein-1 and alpha-smooth muscle actin production, all of which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression (PMID: 33138205). Indoxyl sulfate is also a known cardiotoxin (PMID: 30200452). In plasma, indoxyl sulfate induces endothelial dysfunction by inhibiting endothelial proliferation and migration as well as disrupting wound repair in vitro (PMID: 14717914). Indoxyl sulfate is known to impair angiogenesis by suppressing endothelial cell tube formation and endothelial cell proliferation via chronic aryl hydrocarbon receptor (AhR) activation. Many studies suggest that indoxyl sulfate increases oxidative stress which further exacerbates endothelial dysfunction (PMID: 20876676). This ultimately leads to atherosclerosis, peripheral artery disease and cardiovascular disease, which are common in patients with CKD (PMID: 33456671). In hemodialyzed patients, serum levels of indoxyl sulfate are associated with levels of pentosidine, a marker of carbonyl and oxidative stress (PMID: 14524578). In vitro, indoxyl sulfate increases reactive oxygen species (ROS) production in tubular cells and increases NAD(P)H oxidase activity in endothelial cells (PMID: 29976888). Indoxyl sulfate also strongly decreases the levels of glutathione, one of the most active antioxidant systems of the cell (PMID: 29474405). In addition to its well-known renal toxicity and cardiotoxicity, indoxyl sulfate appears to have osteotoxic, myotoxic and neurotoxic effects. As an osteotoxin, indoxyl sulfate impairs osteoblast function and induces abnormalities of bone turnover (PMID: 28781957). Indoxyl sulfate appears to induce low-turnover bone disease by directly acting on both osteoblasts and osteoclast precursors to suppress bone formation and bone resorption. In vitro studies with mouse osteoblasts have shown that indoxyl sulfate suppresses the gene expression of osterix, osteocalcin, and bone morphogenetic protein 2 (BMP2), thereby inhibiting the formation of mineralized bone nodules, leading to suppressed bone formation (PMID: 28781957). As a myotoxin, indoxyl sulfate appears to induce sarcopenia, which is especially common in patients with CKD. In particular, indoxyl sulfate increases the production of several factors related to skeletal muscle breakdown, including reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-β1) (PMID: 27549031). It also enhances the production of muscle atrophy-related genes, myostatin and atrogin-1 (PMID: 27549031). As a neurotoxin, indoxyl sulfate appears to disrupt the blood brain barrier. In particular, indoxyl sulfate binds to the aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system. The binding of indoxyl sulfate to the AhR leads to blood-brain barrier disruption, which is associated with cognitive impairment in animal models of CKD (PMID: 32527975). Indoxyl sulfate, along with quinolinic acid and kynurenine, are significantly elevated in blood/plasma of individuals with dementia (PMID: 34493657). Recently, indoxyl sulfate has been shown to be associated with altered neural processing (as shown by functional MRI) and the serum abundance of indoxyl sulfate is positively correlated with severity of psychic anxiety in humans (PMID: 34697401). 1H-indol-3-yl Hydrogen sulfate 1H-indol-3-yl Hydrogen sulphate 3-Indolyl hydrogen sulfate 3-Indolyl hydrogen sulfuric acid 3-Indolyl hydrogen sulphate 3-Indolyl hydrogen sulphuric acid 3-Indolyl sulfate 3-Indolyl sulfuric acid 3-Indolyl sulphate 3-Indolyl sulphuric acid 3-Indoxyl sulfate 3-Indoxyl sulfuric acid 3-Indoxyl sulphate 3-Indoxyl sulphuric acid 3-Indoxylsulfate 3-Indoxylsulfuric acid 3-Indoxylsulphate 3-Indoxylsulphuric acid Indican Indol-3-ol indol-3-yl Hydrogen sulfate indol-3-yl Hydrogen sulfuric acid indol-3-yl Hydrogen sulphate indol-3-yl Hydrogen sulphuric acid Indol-3-yl sulfate indol-3-yl Sulfuric acid indol-3-yl sulphate indol-3-yl Sulphuric acid Indoxyl sulfic acid Indoxyl sulfuric acid Indoxyl sulphate Indoxyl sulphuric acid Indoxylsulfate Indoxylsulfuric acid Indoxylsulphate Indoxylsulphuric acid C8H7NO4S 213.21 213.009578407 (1H-indol-3-yl)oxidanesulfonic acid 3-sulfooxy-1H-indole 487-94-5 OS(=O)(=O)OC1=CNC2=CC=CC=C12 InChI=1S/C8H7NO4S/c10-14(11,12)13-8-5-9-7-4-2-1-3-6(7)8/h1-5,9H,(H,10,11,12) BXFFHSIDQOFMLE-UHFFFAOYSA-N belongs to the class of organic compounds known as arylsulfates. These are organic compounds containing a sulfate group that carries an aryl group through an ether group. Arylsulfates Organic compounds Organic acids and derivatives Organic sulfuric acids and derivatives Arylsulfates Aromatic heteropolycyclic compounds Azacyclic compounds Benzenoids Heteroaromatic compounds Hydrocarbon derivatives Indoles Organic oxides Organonitrogen compounds Organooxygen compounds Organopnictogen compounds Substituted pyrroles Sulfuric acid monoesters Aromatic heteropolycyclic compound Arylsulfate Azacycle Benzenoid Heteroaromatic compound Hydrocarbon derivative Indole Indole or derivatives Organic nitrogen compound Organic oxide Organic oxygen compound Organoheterocyclic compound Organonitrogen compound Organooxygen compound Organopnictogen compound Pyrrole Substituted pyrrole Sulfate-ester Sulfuric acid ester Sulfuric acid monoester aryl sulfate indoles Solid logp -0.48 ALOGPS logs -2.43 ALOGPS solubility 7.87e-01 g/l ALOGPS logp 1.29 ChemAxon pka_strongest_acidic -1.8 ChemAxon iupac (1H-indol-3-yl)oxidanesulfonic acid ChemAxon average_mass 213.21 ChemAxon mono_mass 213.009578407 ChemAxon smiles OS(=O)(=O)OC1=CNC2=CC=CC=C12 ChemAxon formula C8H7NO4S ChemAxon inchi InChI=1S/C8H7NO4S/c10-14(11,12)13-8-5-9-7-4-2-1-3-6(7)8/h1-5,9H,(H,10,11,12) ChemAxon inchikey BXFFHSIDQOFMLE-UHFFFAOYSA-N ChemAxon polar_surface_area 79.39 ChemAxon refractivity 49.12 ChemAxon polarizability 19.37 ChemAxon rotatable_bond_count 2 ChemAxon acceptor_count 3 ChemAxon donor_count 2 ChemAxon physiological_charge -1 ChemAxon formal_charge 0 ChemAxon Metabolism and Physiological Effects of Indoxyl Sulfate SMP0123237 Specdb::NmrTwoD 1421 Specdb::CMs 600 Specdb::CMs 601 Specdb::CMs 602 Specdb::CMs 7055 Specdb::CMs 155059 Specdb::NmrOneD 1475 Specdb::NmrOneD 7382 Specdb::NmrOneD 7383 Specdb::NmrOneD 7384 Specdb::NmrOneD 7385 Specdb::NmrOneD 7386 Specdb::NmrOneD 7387 Specdb::NmrOneD 7388 Specdb::NmrOneD 7389 Specdb::NmrOneD 7390 Specdb::NmrOneD 7391 Specdb::NmrOneD 7392 Specdb::NmrOneD 7393 Specdb::NmrOneD 7394 Specdb::NmrOneD 7395 Specdb::NmrOneD 7396 Specdb::NmrOneD 7397 Specdb::NmrOneD 7398 Specdb::NmrOneD 7399 Specdb::NmrOneD 7400 Specdb::NmrOneD 7401 Specdb::MsMs 945 Specdb::MsMs 946 Specdb::MsMs 947 Specdb::MsMs 4373 Specdb::MsMs 4374 Specdb::MsMs 4375 Specdb::MsMs 4376 Specdb::MsMs 4377 Specdb::MsMs 4381 Specdb::MsMs 251478 Specdb::MsMs 251479 Specdb::MsMs 251480 Specdb::MsMs 271419 Specdb::MsMs 271420 Specdb::MsMs 271421 Specdb::MsMs 438002 Specdb::MsMs 438003 Specdb::MsMs 438004 Specdb::MsMs 438005 Specdb::MsMs 438006 Specdb::MsMs 439223 Specdb::MsMs 451934 Specdb::MsMs 2231973 Specdb::MsMs 2253144 Specdb::MsMs 2253334 HMDB00682 16700 IOS #<Reference:0x000055ce30d376e8> #<Reference:0x000055ce30d37530> #<Reference:0x000055ce30d37378> #<Reference:0x000055ce30d371c0> #<Reference:0x000055ce30d37008> #<Reference:0x000055ce30d36e50> #<Reference:0x000055ce30d36c98> Anatidae Type 1 specific Anatidae 8830 Beefalo Type 1 specific Bos taurus X Bison bison 297284 Bison Type 1 specific Bison bison 9901 Buffalo Type 1 specific Bubalus bubalis 89462 Cattle (Beef, Veal) Type 1 specific Bos taurus 9913 Chicken Type 1 specific Gallus gallus 9031 Columbidae (Dove, Pigeon) Type 1 specific Columbidae 8930 Deer Type 1 specific Cervidae 9850 Domestic goat Type 1 specific Capra aegagrus hircus 9925 Domestic pig Type 1 specific Sus scrofa domestica 9825 Elk Type 1 specific Cervus canadensis 1574408 Emu Type 1 specific Dromaius novaehollandiae 8790 European rabbit Type 1 specific Oryctolagus 9984 Greylag goose Type 1 specific Anser anser 8843 Guinea hen Type 1 specific Numida meleagris 8996 Horse Type 1 specific Equus caballus 9796 Mallard duck Type 1 specific Anas platyrhynchos 8839 Mountain hare Type 1 specific Lepus timidus 62621 Mule deer Type 1 specific Odocoileus 9871 Ostrich Type 1 specific Struthio camelus 8801 Pheasant Type 1 specific Phasianus colchicus 9054 Quail Type 1 specific Phasianidae 9005 Rabbit Type 1 specific Leporidae 9979 Rock ptarmigan Type 1 specific Lagopus muta 64668 Sheep (Mutton, Lamb) Type 1 specific Ovis aries 9940 Squab Type 1 specific Columba 8931 Turkey Type 1 specific Meleagris gallopavo 9103 Velvet duck Type 1 specific Melanitta fusca 371864 Wild boar Type 1 specific Sus scrofa 9823