1.02011-09-21 00:09:41 UTC2021-12-06 18:12:33 UTCFDB022179Indoxyl sulfateIndoxyl 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 sulfate1H-indol-3-yl Hydrogen sulphate3-Indolyl hydrogen sulfate3-Indolyl hydrogen sulfuric acid3-Indolyl hydrogen sulphate3-Indolyl hydrogen sulphuric acid3-Indolyl sulfate3-Indolyl sulfuric acid3-Indolyl sulphate3-Indolyl sulphuric acid3-Indoxyl sulfate3-Indoxyl sulfuric acid3-Indoxyl sulphate3-Indoxyl sulphuric acid3-Indoxylsulfate3-Indoxylsulfuric acid3-Indoxylsulphate3-Indoxylsulphuric acidIndicanIndol-3-olindol-3-yl Hydrogen sulfateindol-3-yl Hydrogen sulfuric acidindol-3-yl Hydrogen sulphateindol-3-yl Hydrogen sulphuric acidIndol-3-yl sulfateindol-3-yl Sulfuric acidindol-3-yl sulphateindol-3-yl Sulphuric acidIndoxyl sulfic acidIndoxyl sulfuric acidIndoxyl sulphateIndoxyl sulphuric acidIndoxylsulfateIndoxylsulfuric acidIndoxylsulphateIndoxylsulphuric acidC8H7NO4S213.21213.009578407(1H-indol-3-yl)oxidanesulfonic acid3-sulfooxy-1H-indole487-94-5OS(=O)(=O)OC1=CNC2=CC=CC=C12InChI=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.ArylsulfatesOrganic compoundsOrganic acids and derivativesOrganic sulfuric acids and derivativesArylsulfatesAromatic heteropolycyclic compoundsAzacyclic compoundsBenzenoidsHeteroaromatic compoundsHydrocarbon derivativesIndolesOrganic oxidesOrganonitrogen compoundsOrganooxygen compoundsOrganopnictogen compoundsSubstituted pyrrolesSulfuric acid monoestersAromatic heteropolycyclic compoundArylsulfateAzacycleBenzenoidHeteroaromatic compoundHydrocarbon derivativeIndoleIndole or derivativesOrganic nitrogen compoundOrganic oxideOrganic oxygen compoundOrganoheterocyclic compoundOrganonitrogen compoundOrganooxygen compoundOrganopnictogen compoundPyrroleSubstituted pyrroleSulfate-esterSulfuric acid esterSulfuric acid monoesteraryl sulfateindolesSolidlogp-0.48logs-2.43solubility7.87e-01 g/llogp1.29pka_strongest_acidic-1.8iupac(1H-indol-3-yl)oxidanesulfonic acidaverage_mass213.21mono_mass213.009578407smilesOS(=O)(=O)OC1=CNC2=CC=CC=C12formulaC8H7NO4SinchiInChI=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)inchikeyBXFFHSIDQOFMLE-UHFFFAOYSA-Npolar_surface_area79.39refractivity49.12polarizability19.37rotatable_bond_count2acceptor_count3donor_count2physiological_charge-1formal_charge0Specdb::NmrTwoD1421Specdb::CMs600Specdb::CMs601Specdb::CMs602Specdb::CMs7055Specdb::CMs155059Specdb::NmrOneD1475Specdb::NmrOneD7382Specdb::NmrOneD7383Specdb::NmrOneD7384Specdb::NmrOneD7385Specdb::NmrOneD7386Specdb::NmrOneD7387Specdb::NmrOneD7388Specdb::NmrOneD7389Specdb::NmrOneD7390Specdb::NmrOneD7391Specdb::NmrOneD7392Specdb::NmrOneD7393Specdb::NmrOneD7394Specdb::NmrOneD7395Specdb::NmrOneD7396Specdb::NmrOneD7397Specdb::NmrOneD7398Specdb::NmrOneD7399Specdb::NmrOneD7400Specdb::NmrOneD7401Specdb::MsMs945Specdb::MsMs946Specdb::MsMs947Specdb::MsMs4373Specdb::MsMs4374Specdb::MsMs4375Specdb::MsMs4376Specdb::MsMs4377Specdb::MsMs4381Specdb::MsMs251478Specdb::MsMs251479Specdb::MsMs251480Specdb::MsMs271419Specdb::MsMs271420Specdb::MsMs271421Specdb::MsMs438002Specdb::MsMs438003Specdb::MsMs438004Specdb::MsMs438005Specdb::MsMs438006Specdb::MsMs439223Specdb::MsMs451934Specdb::MsMs2231973Specdb::MsMs2253144Specdb::MsMs2253334HMDB0068216700IOS#<Reference:0x00005556741a3ae0>#<Reference:0x00005556741a3900>#<Reference:0x00005556741a3720>#<Reference:0x00005556741a34f0>#<Reference:0x00005556741a3298>#<Reference:0x00005556741a3040>#<Reference:0x00005556741a2de8>AnatidaeType 1specificAnatidae8830BeefaloType 1specificBos taurus X Bison bison297284BisonType 1specificBison bison9901BuffaloType 1specificBubalus bubalis89462Cattle (Beef, Veal)Type 1specificBos taurus9913ChickenType 1specificGallus gallus9031Columbidae (Dove, Pigeon)Type 1specificColumbidae8930DeerType 1specificCervidae9850Domestic goatType 1specificCapra aegagrus hircus9925Domestic pigType 1specificSus scrofa domestica9825ElkType 1specificCervus canadensis1574408EmuType 1specificDromaius novaehollandiae8790European rabbitType 1specificOryctolagus9984Greylag gooseType 1specificAnser anser8843Guinea henType 1specificNumida meleagris8996HorseType 1specificEquus caballus9796Mallard duckType 1specificAnas platyrhynchos8839Mountain hareType 1specificLepus timidus62621Mule deerType 1specificOdocoileus9871OstrichType 1specificStruthio camelus8801PheasantType 1specificPhasianus colchicus9054QuailType 1specificPhasianidae9005RabbitType 1specificLeporidae9979Rock ptarmiganType 1specificLagopus muta64668Sheep (Mutton, Lamb)Type 1specificOvis aries9940SquabType 1specificColumba8931TurkeyType 1specificMeleagris gallopavo9103Velvet duckType 1specificMelanitta fusca371864Wild boarType 1specificSus scrofa9823