Cyclosporine cellular mechanisms

Meyer-Lehnert H, Bokemeyer D, Eriedrichs U, Backer A, Kramer HJ. Cellular mechanisms of cyclosporine A-associated side-effects role of endotheiin. Kidney Int SuppI 1997 61 S27-S31. 

The search for a common mechanism of action cf the immunosuppressive drugs cyclosporin (CsA) (7)and FK-506 (8)highlights another possibility in which the drug was I discovaed by screening in cellular or in vivo models but the exact mechanism or site of I action is unknown (157). Using the active mol-I ecules, cyclophilin (CyP) and the FK binding protein (FKBP)were identified as the specific receptors for cyclosporin and FK-506, respec-I lively. These binding proteins were discovered to be distinct and inhibitor-specific cis-trans peptidyl-prolyl isomerases that catalyze the... 

FK506 (tacrolimus) (23) is a 23-membered macrocyclic lactone isolated from Streptomyces tsukubaensis and is structurally related to rapamycin. It displays antifungal and immunosuppressive activities. It is marketed as an immunosuppressant that can be used in transplant therapy and several autoimmune disorders. Rapamycin and FK506 share the same common cellular receptor FKBP, but they present a different mechanism of action. Similar to cyclosporine A, FK506 suppresses T-cell activation at the level of lymphokine production and prevents the expression of the interleukin 2 receptor (IL-2R). ... 

The mechanisms of kidney injury include direct tubular epithelial cell toxicity with increased tubular permeability and necrosis, as well as arterial vasoconstriction and ischemic injury (Fanos and Cataldi 2000). Overall, the combined effects of increased cell energy and oxygen requirements due to greater cell membrane permeability, and reduced cellular oxygen delivery due to renal vasoconstriction, results in renal medullary tubular epithelial cell necrosis and kidney injury. Risk factors include CKD, higher average daily doses, volume depletion, and concomitant administration of diuretics and other nephrotoxins (e.g., cyclosporine) (Deray 2002 Costa and Nucci 2001). Rapid infusions of amphotericin B have the potential... 

Hymenistatin 1 (HS-1), cyclo-(-Pro-Pro-Tyr-Val-Pro-Leu-Ile-Ile-), a cyclic 8-peptide isolated from the Hymeniaddon sponge, and totally synthesized in 1993. It causes an immunosuppressive effect in the humoral and cellular immune responses comparable to the action of cyclosporin A (CsA). Based on studies of the comparative influence of HS-1 and CsA on cytokine production, it could be concluded that the mechanisms of interaction with the immune system are different for the two compounds [R. K. Konat et al, Helv. Chim. Acta 1993, 76,1649 M. Cebratetal., Peptides 1996, 27, 191]. 

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