Indoxyl sulfate

Indoxyl sulfate, also known as 3-indoxylsulfate and 3-indoxylsulfuric acid, is a metabolite of dietary L-tryptophan that acts as a cardiotoxin and uremic toxin.^[1][2][3] High concentrations of indoxyl sulfate in blood plasma are known to be associated with the development and progression of chronic kidney disease and vascular disease in humans.^[1][2][3] As a uremic toxin, it stimulates glomerular sclerosis and renal interstitial fibrosis.^[1][2]

Indoxyl sulfate

Names
Preferred IUPAC name 1H-Indol-3-yl hydrogen sulfate
Other names 3-Indoxylsulfate; 3-Indoxylsulfuric acid; Indol-3-yl sulfate
Identifiers
CAS Number	487-94-5 N
3D model (JSmol)	Interactive image
ChEBI	CHEBI:43355
ChEMBL	ChEMBL1233636
ChemSpider	9840
DrugBank	DB07992
PubChem CID	10258
UNII	KT0QA88913
CompTox Dashboard (EPA)	DTXSID701043787 DTXSID30928203, DTXSID701043787
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) Key: BXFFHSIDQOFMLE-UHFFFAOYSA-N
SMILES C1=CC=C2C(=C1)C(=CN2)OS(=O)(=O)O
Properties
Chemical formula	C8H7NO4S
Molar mass	213.21 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Biosynthesis

Indoxyl sulfate is a metabolite of dietary L-tryptophan that is synthesized through the following metabolic pathway:^[3][4][5]

L-tryptophan → indole → indoxyl → indoxyl sulfate

Indole is produced from L-tryptophan in the human intestine via tryptophanase-expressing gastrointestinal bacteria.^[3] Indoxyl is produced from indole via enzyme-mediated hydroxylation in the liver;^[3][4] in vitro experiments with rat and human liver microsomes suggest that the CYP450 enzyme CYP2E1 hydroxylates indole into indoxyl.^[4] Subsequently, indoxyl is converted into indoxyl sulfate by sulfotransferase enzymes in the liver;^[4][5] based upon in vitro experiments with recombinant human sulfotransferases, SULT1A1 appears to be the primary sulfotransferase enzyme involved in the conversion of indoxyl into indoxyl sulfate.^[5]

Tryptophan metabolism by human gut microbiota ( v t e ) Tryptophan Clostridium sporogenes Lacto- bacilli Tryptophanase- expressing bacteria IPA I3A Indole Liver Brain IPA I3A Indole Indoxyl sulfate AST-120 AhR Intestinal immune cells Intestinal epithelium PXR Mucosal homeostasis: ↓TNF-α ↑Junction protein- coding mRNAs L cell GLP-1 T J Neuroprotectant: ↓Activation of glial cells and astrocytes ↓4-Hydroxy-2-nonenal levels ↓DNA damage –Antioxidant –Inhibits β-amyloid fibril formation Maintains mucosal reactivity: ↑IL-22 production Associated with vascular disease: ↑Oxidative stress ↑Smooth muscle cell proliferation ↑Aortic wall thickness and calcification Associated with chronic kidney disease: ↑Renal dysfunction –Uremic toxin Kidneys This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.[3] Indole is produced from tryptophan by bacteria that express tryptophanase.[3] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),[6] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[3][7][8] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[3] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.[3] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.[3] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.[3] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.[3] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[3]

Clinical significance

Occasionally in urinary tract infections, bacteria produce indoxyl phosphatase which splits indoxyl sulfate forming indigo and indirubin creating dramatic purple urine.^[9] Indoxyl sulfate is also a product of indole metabolism, which is produced from tryptophan by intestinal flora, such as Escherichia coli.^[10]