Identification

Name
Chromic citrate
Accession Number
DB14526  (DBSALT002354)
Type
Small Molecule
Groups
Experimental
Description
Not Available
Structure
Thumb
Synonyms
Not Available
Categories
Not Available
UNII
LQC76G8WUE
CAS number
57072-40-9
Weight
Average: 241.095
Monoisotopic: 240.944034
Chemical Formula
C6H5CrO7
InChI Key
SWXXYWDHQDTFSU-UHFFFAOYSA-K
InChI
InChI=1S/C6H8O7.Cr/c7-3(8)1-6(13,5(11)12)2-4(9)10;/h13H,1-2H2,(H,7,8)(H,9,10)(H,11,12);/q;+3/p-3
IUPAC Name
chromium(3+) 2-hydroxypropane-1,2,3-tricarboxylate
SMILES
[Cr+3].OC(CC([O-])=O)(CC([O-])=O)C([O-])=O

Pharmacology

Indication

Indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN), to maintain chromium serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms [Label].

Pharmacodynamics

Trivalent chromium is part of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Chromium increases insulin binding to cells, increases insulin receptor density and activates insulin receptor kinase leading to enhanced insulin sensitivity [2]. In chromium deficiency, intravenous administration of chromium resulted in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency [Label].

Mechanism of action

Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules [3]. Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake [3]. Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt.

Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein [3]. As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells [8]. Chromium attenuates the activity of PTP-1B in vitro, which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling [3]. Transient upregulation of AMPK by chromium also leads to increased glucose uptake [3].

TargetActionsOrganism
UCytochrome b5Not AvailableHuman
Absorption

Chromium compounds are both absorbed by the lung and the gastrointestinal tract. Oral absorption of chromium compounds in humans can range between 0.5% and 10%, with the hexavalent (VI) chromium more easily absorbed than the trivalent (III) form [5]. Absorption of chromium from the intestinal tract is low, ranging from less than 0.4% to 2.5% of the amount consumed [7]. Vitamin C and the vitamin B niacin is reported to enhance chromium absorption [7].

Most hexavalent Cr (VI) undergoes partial intragastric reduction to Cr (III) upon absorption, which is an action mainly mediated by sulfhydryl groups of amino acids [5]. Cr (VI) readily penetrates cell membranes and chromium can be found in both erythrocytes and plasma after gastrointestinal absorption of Cr (IV). In comparison, the presence of chromium is limited to the plasma as Cr (III) displays poor cell membrane penetration [5]. Once transported through the cell membrane, Cr (VI) is rapidly reduced to Cr (III), which subsequently binds to macromolecules or conjugate with proteins. Cr (III) may be bound to transferrin or other plasma proteins, or as complexes, such as glucose tolerance factor (GTF).

Volume of distribution

Absorbed chromium is distributed to all tissues of the body and its distribution in the body depends on the species, age, and chemical form [8]. Circulating Cr (III) following oral or parenteral administration of different compounds can be taken up by tissues and accumulates in the liver, kidney, spleen, soft tissue, and bone [7].

Protein binding

In the blood, 95% of chromium (III) is bound to large molecular mass proteins, such as transferrin, while a small proportion associates with low molecular mass oligopeptides [6]. Serum chromium is bound to transferrin in the beta globulin fraction [Label].

Metabolism

The metabolism of Cr (VI) involves reduction by small molecules and enzyme systems to generate Cr (III) and reactive intermediates. During this process, free radicals can be generated, which is thought to induce damage of cellular components and cause toxicity of chromium [6]. The metabolites bind to cellular constituents [5].

Route of elimination

Absorbed chromium is excreted mainly in the urine, accounting for 80% of total excretion of chromium; small amounts are lost in hair, perspiration and bile [5]. Chromium is excreted primarily in the urine by glomerular filtration or bound to a low molecular-weight organic transporter [8].

Half life

The elimination half-life of hexavalent chromium is 15 to 41 hours [5].

Clearance

Excretion of chromium is via the kidneys ranges from 3 to 50 μg/day [Label]. The 24-hour urinary excretion rates for normal human subjects are reported to be 0.22 μg/day [8].

Toxicity

Oral LD50 for Cr (VI) is 135 - 175 mg/kg in mouse and 46 - 113 mg/kg in rat [5]. Oral LD50 for Cr (III) in rat is >2000 mg/kg [5]. LD50 of chromium (III) oxide in rats is reported to be > 5g/kg [6]. Other LD50 values reported for rats include: 3.5 g/kg (CI 3.19-3.79 g/kg) for chromium sulphate; 11.3 g/kg for chromium (III) acetate; 3.3 g/kg for chromium nitrate; and 1.5 g/kg for chromium nitrate nonahydrate [6].

Acute overdose of chromium is rare and seriously detrimental effects of hexavalent chromium are primarily the result of chronic low-level exposure [5]. In case of overdose with minimal toxicity following acute ingestion, treatment should be symptomatic and supportive [5]. There is no known antidote for chromium toxicity.

Hexavalent chromium is a Class A carcinogen by the inhalation route of exposure and Class D by the oral route [5]. The oral lethal dose in humans has been estimated to be 1-3 g of Cr (VI); oral toxicity most likely involves gastrointestinal bleeding rather than systemic toxicity [5]. Chronic exposure may cause damage to the following organs: kidneys, lungs, liver, upper respiratory tract [MSDS]. Soluble chromium VI compounds are human carcinogens. Hexavalent chromium compounds were mutagenic in bacteria assays and caused chromosome aberrations in mammalian cells. There have been associations of increased frequencies of chromosome aberrations in lymphocytes from chromate production workers [4]. In human cells in vitro, Cr (VI) caused chromosomal aberrations, sister chromatid exchanges and oxidative DNA damage [5].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Chromic citrate which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Wallach S: Clinical and biochemical aspects of chromium deficiency. J Am Coll Nutr. 1985;4(1):107-20. [PubMed:3886757]
  2. Anderson RA: Chromium in the prevention and control of diabetes. Diabetes Metab. 2000 Feb;26(1):22-7. [PubMed:10705100]
  3. Hua Y, Clark S, Ren J, Sreejayan N: Molecular mechanisms of chromium in alleviating insulin resistance. J Nutr Biochem. 2012 Apr;23(4):313-9. doi: 10.1016/j.jnutbio.2011.11.001. [PubMed:22423897]
  4. CHROMIUM, ELEMENTAL - National Library of Medicine HSDB ... - Toxnet - NIH [Link]
  5. CHROMIUM COMPOUNDS - National Library of Medicine HSDB ... - Toxnet - NIH [Link]
  6. Chromium Toxicological Overview - Health Protection Agency - Gov.uk [Link]
  7. Dietary Supplement Fact Sheet: Chromium [Link]
  8. Dailymed Label: DIVISTA - chromium picolinate capsule [Link]
External Links
ChemSpider
4955809

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.01 mg/mLALOGPS
logP1.08ALOGPS
logP-1.3ChemAxon
logS-2.2ALOGPS
pKa (Strongest Acidic)3.05ChemAxon
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge-3ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area140.62 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity68.14 m3·mol-1ChemAxon
Polarizability14.23 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as tricarboxylic acids and derivatives. These are carboxylic acids containing exactly three carboxyl groups.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Tricarboxylic acids and derivatives
Direct Parent
Tricarboxylic acids and derivatives
Alternative Parents
Tertiary alcohols / Carboxylic acid salts / Carboxylic acids / Organic oxides / Organic chromium salts / Hydrocarbon derivatives / Carbonyl compounds / Organic cations
Substituents
Tricarboxylic acid or derivatives / Tertiary alcohol / Carboxylic acid salt / Organic transition metal salt / Carboxylic acid / Organic oxygen compound / Organic chromium salt / Organic oxide / Hydrocarbon derivative / Organic salt
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Metal ion binding
Specific Function
Cytochrome b5 is a membrane bound hemoprotein which function as an electron carrier for several membrane bound oxygenases.
Gene Name
CYB5A
Uniprot ID
P00167
Uniprot Name
Cytochrome b5
Molecular Weight
15329.985 Da
References
  1. Jannetto PJ, Antholine WE, Myers CR: Cytochrome b(5) plays a key role in human microsomal chromium(VI) reduction. Toxicology. 2001 Feb 28;159(3):119-33. [PubMed:11223168]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transferrin receptor binding
Specific Function
Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from si...
Gene Name
TF
Uniprot ID
P02787
Uniprot Name
Serotransferrin
Molecular Weight
77063.195 Da
References
  1. Moshtaghie AA, Ani M, Bazrafshan MR: Comparative binding study of aluminum and chromium to human transferrin. Effect of iron. Biol Trace Elem Res. 1992 Jan-Mar;32:39-46. [PubMed:1375080]

Drug created on July 12, 2018 13:26 / Updated on November 02, 2018 07:54