title: Reduction of ciclosporin and tacrolimus nephrotoxicity by plant polyphenols.
abstract: The immunosuppressants ciclosporin (cyclosporin A, CsA) and tacrolimus can cause severe nephrotoxicity. Since CsA increases free radical formation, this study investigated whether an extract from Camellia sinensis, which contains several polyphenolic free radical scavengers, could prevent nephrotoxicity caused by CsA and tacrolimus. Rats were fed powdered diet containing polyphenolic extract (0-0.1%) starting 3 days before CsA or tacrolimus. Free radicals were trapped with alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) and measured using an electron spin resonance spectrometer. Both CsA and tacrolimus decreased glomerular filtration rates (GFR) and caused tubular atrophy, vacuolization and calcification and arteriolar hyalinosis, effects that were blunted by treatment with dietary polyphenols. Moreover, CsA and tacrolimus increased POBN/radical adducts in urine nearly 3.5 fold. Hydroxyl radicals attack dimethyl sulfoxide (DMSO) to produce a methyl radical fragment. Administration of CsA or tacrolimus with (12)C-DMSO produced a 6-line spectrum, while CsA or tacrolimus given with (13)C-DMSO produced a 12-line ESR spectrum, confirming formation of hydroxyl radicals. 4-Hydroxynonenal (4-HNE), a product of lipid peroxidation, accumulated in proximal and distal tubules after CsA or tacrolimus treatment. ESR changes and 4-HNE formation were largely blocked by polyphenols. Taken together, these results demonstrate that both CsA and tacrolimus stimulate free radical production in the kidney, most likely in tubular cells, and that polyphenols minimize nephrotoxicity by scavenging free radicals.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA. zhong@musc.edu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhong
authors.forename: Henry D
authors.initials: HD
authors.lastname: Connor
authors.forename: Xiangli
authors.initials: X
authors.lastname: Li
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mason
authors.forename: Donald T
authors.initials: DT
authors.lastname: Forman
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D028241:Camellia sinensis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000097:blood / Q000633:toxicity*; D005419:Flavonoids / Q000008:administration & dosage / Q000627:therapeutic use*; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000652:urine; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D000069463:Olive Oil; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use*; D008517:Phytotherapy; D010938:Plant Oils / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D059808:Polyphenols; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000097:blood / Q000633:toxicity*
chemical_list: D000447:Aldehydes; D005419:Flavonoids; D005609:Free Radicals; D007166:Immunosuppressive Agents; D000069463:Olive Oil; D010636:Phenols; D010938:Plant Oils; D059808:Polyphenols; C000515:cremophor EL; D016572:Cyclosporine; C027576:4-hydroxy-2-nonenal; D005990:Glycerol; D016559:Tacrolimus