ChemFOnt: Showing chemical card for Indoxyl sulfate (CFc000000536)

Record Information

Version

1.0

Creation Date

2022-08-28 10:25:12 UTC

Update Date

2022-09-13 18:44:57 UTC

Chemfont ID

CFc000000536

Molecule Identification

Common Name

Indoxyl sulfate

Definition

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 ).

Structure

MOL SDF PDB SMILES InChI

Synonyms

Value	Source
3-Indolyl hydrogen sulfate	ChEBI
3-Indolyl sulfate	ChEBI
3-Indoxyl sulfate	ChEBI
3-Indoxylsulfuric acid	ChEBI
Indican	ChEBI
indol-3-yl Hydrogen sulfate	ChEBI
indol-3-yl Sulfate	ChEBI
indol-3-yl Sulphate	ChEBI
Indoxyl sulfic acid	ChEBI
Indoxyl sulphate	ChEBI
Indoxyl-3-sulphate	ChEBI
Indoxylsulfuric acid	ChEBI
3-Indolyl hydrogen sulfuric acid	Generator
3-Indolyl hydrogen sulphate	Generator
3-Indolyl hydrogen sulphuric acid	Generator
3-Indolyl sulfuric acid	Generator
3-Indolyl sulphate	Generator
3-Indolyl sulphuric acid	Generator
3-Indoxyl sulfuric acid	Generator
3-Indoxyl sulphate	Generator
3-Indoxyl sulphuric acid	Generator
3-Indoxylsulfate	Generator
3-Indoxylsulphate	Generator
3-Indoxylsulphuric acid	Generator
indol-3-yl Hydrogen sulfuric acid	Generator
indol-3-yl Hydrogen sulphate	Generator
indol-3-yl Hydrogen sulphuric acid	Generator
indol-3-yl Sulfuric acid	Generator
indol-3-yl Sulphuric acid	Generator
Indoxyl sulfuric acid	Generator
Indoxyl sulphuric acid	Generator
Indoxyl-3-sulfate	Generator
Indoxyl-3-sulfuric acid	Generator
Indoxyl-3-sulphuric acid	Generator
Indoxylsulfate	Generator
Indoxylsulphate	Generator
Indoxylsulphuric acid	Generator
1H-indol-3-yl Hydrogen sulfate	HMDB
1H-indol-3-yl Hydrogen sulphate	HMDB
indol-3-Ol	HMDB
Indican monosodium salt	HMDB
Monopotassium salt, indican	HMDB
Monosodium salt, indican	HMDB
Sulfate, indoxyl	HMDB
Indican monopotassium salt	HMDB
1H-indol-3-Ol hydrogen sulfate ester	HMDB
3-Sulphooxy-1H-indole	HMDB
Indoxyl sulfate	Generator

Chemical Formula

C₈H₇NO₄S

Average Molecular Weight

213.21

Monoisotopic Molecular Weight

213.009578407

IUPAC Name

(1H-indol-3-yl)oxidanesulfonic acid

Traditional Name

3-sulfooxy-1H-indole

CAS Registry Number

487-94-5

SMILES

OS(=O)(=O)OC1=CNC2=CC=CC=C12

InChI Identifier

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)

InChI Key

BXFFHSIDQOFMLE-UHFFFAOYSA-N

Chemical Taxonomy

Description

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.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Organic sulfuric acids and derivatives

Sub Class

Arylsulfates

Direct Parent

Arylsulfates

Alternative Parents

Substituents

Arylsulfate
Indole
Indole or derivatives
Substituted pyrrole
Sulfuric acid monoester
Sulfate-ester
Sulfuric acid ester
Benzenoid
Pyrrole
Heteroaromatic compound
Organoheterocyclic compound
Azacycle
Organooxygen compound
Organonitrogen compound
Organic oxygen compound
Organic nitrogen compound
Hydrocarbon derivative
Organopnictogen compound
Organic oxide
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

indoles (CHEBI:43355 )
aryl sulfate (CHEBI:43355 )

Functional Ontology

Physiological effect

Health effect

Digestive system disorder

Hepatobiliary disorder

Hepatic disorder

Liver damage (PMID: 31434538)

Nervous system disorder

Nerve damage (PMID: 31434538)
Coma (HMDB: HMDB0000682)

Central nervous system disorder

Psychiatric disorder

Psychosis (HMDB: HMDB0000682)

Neurotic, stress-related, or somatoform disorder

Anxiety (PMID: 34697401)

Mood disorder

Major depressive disorder (PMID: 34697401)

Renal system and urinary system

Renal disorder

Kidney disease (HMDB: HMDB0000682)
Uremia (HMDB: HMDB0000682)
Chronic kidney disease (HMDB: HMDB0000682)

Observation

Circulatory system disorder

Cardiac disorder

Cardiovascular disease (HMDB: HMDB0000682)

Disposition

Biological location

Non-excretory biofluid

Biofluid or Excreta

Blood (PMID: 22626821)
Cerebrospinal Fluid (CSF) (PMID: 31726035)

Tissue substructure

Muscle (HMDB: HMDB0000682)

Organ

Tissue

Muscle tissue

Skeletal muscle (HMDB: HMDB0000682)

Connective tissue

Bone marrow (HMDB: HMDB0000682)

Endothelial tissue (HMDB: HMDB0000682)

Excreta

Biofluid or Excreta

Urine (PMID: 6321058)
Feces (PMID: 27543620)

Cellular substructure

Route of exposure

Parenteral

Dermal (HMDB: HMDB0000682)

Enteral

Ingestion (HMDB: HMDB0000682)

Source

Exogenous

Exogenous (HMDB: HMDB0000682)

Food

Animal origin

Poultry

Pheasant (FooDB: FOOD00430)
Squab (FooDB: FOOD00481)
Turkey (FooDB: FOOD00494)
Quail (FooDB: FOOD00541)
Anatidae (FooDB: FOOD00576)
Rock ptarmigan (FooDB: FOOD00597)
Columbidae (Dove, Pigeon) (FooDB: FOOD00610)
Chicken (FooDB: FOOD00329)
Mallard duck (FooDB: FOOD00353)
Emu (FooDB: FOOD00360)
Greylag goose (FooDB: FOOD00368)
Guinea hen (FooDB: FOOD00373)
Ostrich (FooDB: FOOD00422)
Velvet duck (FooDB: FOOD00427)

Lagomorph

Ovis

Sheep (Mutton, Lamb) (FooDB: FOOD00473)

Bovine

Venison

Deer (FooDB: FOOD00524)
Mule deer (FooDB: FOOD00348)
Elk (FooDB: FOOD00359)

Caprae

Domestic goat (FooDB: FOOD00529)

Swine

Domestic pig (FooDB: FOOD00536)
Wild boar (FooDB: FOOD00307)

Equine

Horse (FooDB: FOOD00378)

Nut

Nuts (HMDB: HMDB0000682)

Milk and milk product

Dairy products (HMDB: HMDB0000682)

Egg

Eggs (HMDB: HMDB0000682)

Soy

Soy (HMDB: HMDB0000682)

Meats (HMDB: HMDB0000682)
Legumes (HMDB: HMDB0000682)

Cereal and cereal product

Cereal product

Whole grain cereal products (HMDB: HMDB0000682)

Endogenous

Endogenous (HMDB: HMDB0000682)

Microbe

Microbe (HMDB: HMDB0000682)
Escherichia coli (HMDB: HMDB0000682)

Process

Not Available

Role

Industrial application

Pharmaceutical industry

Pharmaceutical (HMDB: HMDB0000682)

Biomarker

Eosinophilic esophagitis (MarkerDB: MDB00000217)

Biological role

Physical Properties

Predicted Properties

Property	Value	Source
Water Solubility	0.79 g/L	ALOGPS
logP	-0.48	ALOGPS
logP	1.29	ChemAxon
logS	-2.4	ALOGPS
pKa (Strongest Acidic)	-1.8	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	79.39 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	49.12 m³·mol⁻¹	ChemAxon
Polarizability	19.37 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	Yes	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon