Rhein (also known as Monorhein; NSC 38629; Rheic acid; Rheinic acid) is a naturally occuring anthraquinone compound isolated from the fresh rhizome of Rheum coreanum Nakai, showing anti-inflammation and antitumor activities. Rhein at 35 μM can effectively inhibit the synthesis of IL-1β on human osteoarthritis synovium, as well as the action of this cytokine at the cartilage level, by reducing the number of chondrocyte IL-1R and inhibiting IL-1β induced NO production in chondrocytes and cartilage. Rhein also induces apoptosis in human promyelocytic leukemia cells (HL-60), characterized by caspase activation, poly(ADP)ribose polymerase (PARP) cleavage, and DNA fragmentation.

Physicochemical Properties

Molecular Formula	C15H8O6
Molecular Weight	284.22
Exact Mass	284.032
CAS #	478-43-3
Related CAS #	478-43-3
PubChem CID	10168
Appearance	Light yellow to yellow solid powder
Density	1.7±0.1 g/cm3
Boiling Point	597.8±50.0 °C at 760 mmHg
Melting Point	≥300 °C(lit.)
Flash Point	329.4±26.6 °C
Vapour Pressure	0.0±1.8 mmHg at 25°C
Index of Refraction	1.761
LogP	4.58
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	1
Heavy Atom Count	21
Complexity	487
Defined Atom Stereocenter Count	0
InChi Key	FCDLCPWAQCPTKC-UHFFFAOYSA-N
InChi Code	InChI=1S/C15H8O6/c16-9-3-1-2-7-11(9)14(19)12-8(13(7)18)4-6(15(20)21)5-10(12)17/h1-5,16-17H,(H,20,21)
Chemical Name	4,5-Dihydroxyanthraquinone-2-carboxylic acid
Synonyms	Rhein, Monorhein, NSC-38629, NSC38629,NSC 38629,Rheinic Acid
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	Rhein reduces NB4 cell viability in a dose-dependent manner (0-80 μM, 72 hours) [2]. Rhein (5 μM, 72 hours) enhances the formation of ROS in ATRA-activated NB4 cells, as well as semi-adherent macrophage-like cells and phagocytosis, as well as the expression of CD11b, CD14, CCR-1, and CCR-2 [2]. Rhein (5 μM, 72 hours) inhibits the mTOR pathway and triggers apoptosis in NB4 cells [2]. In MCF-7 and MDA-MB-435 cells, Rhein (50-200 μM, 48 hours) suppresses angiogenesis [4]. HUVEC proliferation, migration, invasion, and tube formation are inhibited by Rhein (0-50 μM, 24 hours) (inhibition of VEGF165, EGF in supernatant, and HIF-1α in nuclear extract) [4].
ln Vivo	In rats, acetaminophen-induced liver and renal damage is prevented by Rhein (10–40 mg/kg, ig) [3].
Cell Assay	RT-PCR[2] Cell Types: acute promyelocytic leukemia (APL) cell (NB4 cells) Tested Concentrations: 5 μM Incubation Duration: 72 h Experimental Results: Increased mRNA expression of PU.1, C/EBPA, and C/EBPE. Increased ATRA activated mRNA expression of CCR1 and CCR2. Western Blot Analysis[2] Cell Types: NB4 cells Tested Concentrations: 0-40 μM Incubation Duration: 48 and 72 h Experimental Results: Increased the expression of cleaved caspase-3, Bax. diminished the expression of Bcl -xl,procaspase-3.
Animal Protocol	Animal/Disease Models: 2.5 g/kg APAP (ig) induced rats[3] Doses: 10, 20 and 40 mg/kg Route of Administration: ig Experimental Results: Ameliorated histopathological damage of liver and kidney. decreased GPT, GOT, UREA and CREA levels and ROS production. Restored NO, MDA, GSH contents.
ADME/Pharmacokinetics	Absorption, Distribution and Excretion Tmax of 1.6-2.6 hours. 37% is excreted in urine and 53% in feces as estimated in rats. 15-60L. Total CL is 1.5 L/h and renal CL is 0.1 L/h. Metabolism / Metabolites Metabolized primarily to rhein glucuronide and rhien sulfate. Biological Half-Life 4-10h.
Toxicity/Toxicokinetics	Protein Binding 99% bound to plasma proteins.
References	[1]. The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis. J Pharmacol Exp Ther. 2015 Oct;355(1):125-34. [2]. Rhein augments ATRA-induced differentiation of acute promyelocytic leukemia cells. Phytomedicine. 2018 Oct 1;49:66-74. [3]. Rhein protects against acetaminophen-induced hepatic and renal toxicity. Food Chem Toxicol. 2011 Aug;49(8):1705-10. [4]. Rhein inhibits angiogenesis and the viability of hormone-dependent and -independent cancer cells under normoxic or hypoxic conditions in vitro. Chem Biol Interact. 2011 Jul 15;192(3):220-32.
Additional Infomation	Pharmacodynamics **Liver: **Reverses animal models of non-alcoholic fatty liver disease by lowering liver lipids and reducing inflammation. Also reverses and prevents fibrosis in liver injury. **Kidney: **Protects against fibrosis in nephropathy models and improves epithelial tight junction function. **Bone and joint:** Decreases inflammation and cartilage destruction and also corrects altered osteoblast acitivity. **Lipid lowering and anti-obesity:** Reduces body weight and fat content, and lowers high density lipoprotein and low density lipoprotein. May prevent adipocyte differentiation. **Anti-oxidant/Pro-oxidant**: Reduces levels of reactive oxygen species (ROS) at concentrations of about 2-16 microM but induces the generation of ROS at concentrations of 50 microM and above. **Anti-cancer:** Rhein has been observed to produce DNA damage and suppress DNA repair in cancer cells. It induces apoptosis via ER stress, calcium, and mitochondria mediated pathways. Rhein also prevents cancer cell invasion into systemic circulation by preventing angiogenesis and breakdown of the extracellular matrix. Finally, rhein suppresses the activation of several tumor promoting signalling pathways. **Anti-inflammatory: ** Suppresses the production of pro-inflammatory cytokines such as interleukin-1beta and interleukin-6. **Anti-diabetic: **Lowers plasma glucose and increases survival of islet beta cells in type 2 diabetes mellitus models. **Anti-microbial:** Inhibits arylamine N-acteyltransferase and cell growth in Helicobacter pylori. Rhien also appears to be effective against many genotypes of Staphylococcus aureus. **Anti-allergenic:** Inhibits production of leukotrienes and the release of histamine from mast cells.

Solubility Data

Solubility (In Vitro)

DMSO:<1 mg/mL Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: 1.67 mg/mL (5.88 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.5184 mL	17.5920 mL	35.1840 mL
	5 mM	0.7037 mL	3.5184 mL	7.0368 mL
	10 mM	0.3518 mL	1.7592 mL	3.5184 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.