Definition
A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.
Description
A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [PubChem]
Top Gene Interactions
Related Pathways
General Information
- Metabolism: Half Life: 57-63 hours
- Uses/Sources: Used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. [Wikipedia]
- Health Effects: Increased susceptibility to infection, lymphoma, and malignancy; bronchial anastomotic dehiscence in lung transplant patients; decline in renal function in long-term combination of cyclosporine with Rapamune; proteinuria. (L1874)
- Symptoms: The most common ( ≥ 30%) adverse reactions observed with Rapamune in clinical studies are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. (L1874)
- Treatment: General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. (L1712)
- Route of Exposure: Oral
Toxicity
- Carcinogenicity: No indication of carcinogenicity to humans (not listed by IARC).
- Toxicity: LD50: >800 mg/kg (oral, rat) (L1874) LD50: >800 mg/kg (oral, mice) (L1874)
Mechanism of Action
Target Name | Mechanism of Action | References |
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Serine/threonine-protein kinase mTOR Fibroblast growth factor 2 Eukaryotic translation initiation factor 4E |
11752352 10843203 12742462 16134928 20427189 20005306 17350953 19620795 |
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Peptidyl-prolyl cis-trans isomerase FKBP1A | Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. |
9383449 11752352 17438408 16134928 9857082 10091702 |