Cyclosporine toxicity to organs other than the kidney.
The molecular basis for CsA toxicity is unknown, and several fundamental questions remain. First, it is still unclear whether the toxicity of CsA is a consequence of its mechanism of action (and therefore perhaps inevitable) or is separate from its beneficial (immunosuppressive) effects. Second, several organs appear to be at greater risk for CsA toxicity, but the mechanisms involved in this increased susceptibility (increased membrane binding of the drug, increased intracellular transport, increased intracellular binding, different metabolism, inefficient protective mechanisms, etc.) have not been studied. Third, and equally important, it is possible that many of the toxicities of CsA are not related to CsA itself (or its metabolites) but to secondary mediators produced in the presence of CsA. This would imply that the study of CsA toxicity in vitro would necessitate the presence of these cells (in addition to the "target" cells) under conditions in which these toxic mediators are formed. There are few answers to these questions at present, and, whilst answers to the first two questions may be obtained from the in vitro study of cell culture systems, the answer to the third requires the development and study of suitable in vivo models of CsA toxicity.
Rush
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Transplant Research Group, Health Sciences Centre, Winnipeg, Manitoba, Canada.
D000591:Amino Acid Isomerases / Q000378:metabolism; D001847:Bone Diseases / Q000139:chemically induced; D002318:Cardiovascular Diseases / Q000139:chemically induced; D002352:Carrier Proteins / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003524:Cyclosporins / Q000009:adverse effects*; D006801:Humans; D009135:Muscular Diseases / Q000139:chemically induced; D009422:Nervous System Diseases / Q000139:chemically induced; D010182:Pancreatic Diseases / Q000139:chemically induced; D019696:Peptidylprolyl Isomerase; D011500:Protein Synthesis Inhibitors; D012871:Skin Diseases / Q000139:chemically induced
D002352:Carrier Proteins; D003524:Cyclosporins; D011500:Protein Synthesis Inhibitors; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase