9,10-Dihydro-4,5-dihydroxy-9,10-dioxoanthracen-2-carbonsure

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Metabolite of Senna

610 °F (NTP, 1992)

>300

321 °C

Rhein appears as yellow needles (from methanol) or yellow-brown powder. (NTP, 1992)

Solid

Warning

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 78 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

**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.

**Liver: **The reversal of non-alcoholic fatty liver disease stems from rhien's lipid lowering and anti-obesity actions which result in an overall decrease in body weight, high density lipoprotein, and low density lipoprotein as well as its anti-inflammatory action. The reversal of hepatic fibrosis is thought to be due to rhien's anti-inflammatory and anti-oxidant action which suppresses the pro-fibrotic signalling from macrophages and further damage from reactive oxygen species respectively. Ultimately this results in reduced expression of alpha-smooth muscle actin (Alpha-SMA) which is indicative of decreased hepatic stellate cell and myofibroblast activation. Rhein also appears to suppress the expression of transforming growth factor-Beta (TGF-Beta) **Kidney: **The protection from fibrosis in the kidney also appears to stem from rhien's anti-inflammatory action resulting in less inflammatory cell infiltration along with suppression of alpha-SMA and fibronectin expression. These indicate a reduction in the activation of interstitial fibroblasts which are responsible for excess production of extracellular matrix components. Rhien may also suppress TGF-beta expression in the kidney. The anti-fibrotic mechanism of rhien may involve the upregulation of bone morphogenetic protein 7 and hepatic growth factor. In diabetic nephropathy rhein appears to suppress the expression of integrin-linked kinase leading to a reduction in the matrix metalloproteinase-9/tissue inhibitor of matrix metalloproteinase-1 ratio. The improvement of epithelial tight junction function seems to involve upregulation of zona occludins protein-1 and occludin expression. **Bone and joint:**Rhein reduces cartilage destruction by decreasing expression of matrix metalloproteinase (MMP)-1 and -3 as well as upregulating tissue inhibitor of matrix metalloproteinases which serve to reduce the activity of several MMPs. The anti-inflammatory action of rhein reduces the level of interleukin-1beta activity which plays a large role in reduction of extracellular matrix production, MMP activity, and continued inflammation. Rhein reduces abnormal osteoblast synthetic activity through an unknown mechanism. **Lipid lowering and anti-obesity: **Rhein is known to bind and inhibit liver X receptor alpha and beta with Kd values of 46.7 microM and 31.97 microM respectively. This decreases the expression of genes such as that of sterol regulatory element binding transcription factor 1 (SREBP1c) and its downstream genes for fatty acid synthase (FAS), steroyl-coenzyme A desaturase 1 (SCD1), and acetyl CoA carboxylase 1 (ACC1). SREBP1c, FAS, SCD1, and ACC1 are all involved in adipogenesis and their suppression results in less fat content. The genes for ABCA1 and ABCG1 are also suppressed. These correspond to cholesterol efflux trasporters and likely explain the reductiion in HDL and LDL seen with rhein. The inhibition of LXR by rhien relieves the inhibition on uncoupling protein 1 expression in brown adipose tissue. The result of this is increased thermogenesis which likely plays a role in the reduction of body weight produced by rhien. Additionally, rhein may downregulate peroxisome proliferator-receptor gamma and its downstream genes to inhibit adipocyte differentiation. **Anti-oxidant/Pro-oxidant:** The antoxidant mechanism is unknown. The pro-oxidant action of rhien may involve the inhibition of mitochondrial respiratory complex 1 and subsequent facilitation of NADH and NADPH dependent lipid peroxidation. **Anti-cancer:** The exact mechanism of rhein's ability to damage DNA and supress the expression of DNA repair enzymes ADR and MGMT is unknown. The mechanism through which rhien induces ER stress is unknown but likely involves its pro-oxidant properties. Rhein has been observed to produce increases in cytosolic calcium, reductions in mitochondrial membrane potential, and upregulation of pro-apoptotic proteins as well as leakage of cytochrome C which would induce apoptosis via the intrinsic pathway. The reduction of matrix metalloproteinase-9 serves to prevent extra cellular matrix breakdown by cancer cells and hinders their invasion into surrounding tissue. Rhein also decreases vascular endothelial growth factor expression through an unknown mechanism to prevent cancer cells from stimulating agiogenesis. Rhein reduces the activity of the nuclear factor kappa (NFkappaB) pathway by preventing the destruction of IKBalpha. The activity of the phosphoinositol 3-kinase/Akt pathway is also reduced by rhien. Rhein's inhibition of the mitogen-activated protein kinase pathways (particularly those involving extracellular signal regulated kinase) appears to follow a U-shaped dose response curve. ERK phosphorylation is inhibited at low concentrations of around 3microM but activated at higher concentrations of around 30microM. Furthermore, ERK phosporylation is again inhibited at extremely high concentrations in excess of 100 microM. The suppression of these three pathways is likely involved in the anti-proliferative effects of rhein. **Anti-inflammatory:** The mechanism of rhein's anti-inflammatory effect likely involves its inhibition of the NFkappa B pathway which plays a role in the production of many pro-inflammatory cytokines. Rhein's anti-oxidant activity may also play a role in preventing damage during inflammation. **Anti-diabetic:** Rhein is thought to increase islet beta cell survival by suppressing the expression of dynamin-related protein 1 and thereby preventing mitochondrial fission. Rhein's anti-oxidant properties are also thought to play a role in protecting islet beta cells. The reduction in plasma glucose is likely due to increased survival of islet beta cells and subsequent increases in insulin secretion. Rhein's anti-inflammatory action may also serve to reduce insulin resistance. **Anti-microbial:** Rhien inhibits H. pylori arylamine N-acetyltransferase in a dose dependent manner. The mechanism of rhein's anti-microbial effect on H. pylori and S. aureus are unknown. **Anti-allergenic:** Rhien inhibits 5-lipoxygenase with an IC50 of 13.7microM. Rhien also inhibits mast cell degranulation although the specific mechanism is unknown.

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.