title: Cyclosporin A-induced lipid and protein oxidation in human B-cells and in Epstein-Barr virus-infected B-cells is prevented by antioxidants.
abstract: The incidence of post-transplant lymphoproliferative disorder (PTLD) has increased since cyclosporin A (CsA) became the mainstay of transplant immunosuppression. We have previously shown that, in addition to its potent immunosuppressive property, CsA-induced oxidative stress plays an important role in Epstein-Barr virus (EBV)-related PTLD. Using lipid hydroperoxide and malondialdehyde as markers of lipid oxidation, and protein carbonyls as markers of protein oxidation, we further investigated the in vitro effect of CsA on human B cells and EBV-infected human B cells. We found that CsA at 500 ng/ml, a relatively safe and effective blood concentration in organ transplant recipients, induced the highest lipid hydroperoxide and malondialdehyde after 10 min of treatment in time- and concentration-related kinetic studies. We also found that treatment with CsA at 500 ng/ml for 10 min increased the EBV-infected B cell protein carbonyl formation as assayed by immunoblot method. CsA-induced lipid and protein oxidation could be inhibited by vitamin E, N-acetyl cysteine, and pyrollidine dithiocarbamate. CsA significantly promoted the EBV-B cell transformation as assayed by colony counting, cell counting, and (3)H-thymidine incorporation. Our recent study provides further evidence to support the hypothesis that CsA exerts direct oxidative stress in EBV-infected as well as non-EBV-infected human B cells. A greater understanding of these cellular and molecular mechanisms may benefit the clinical practice and prevention of PTLD.
authors.affiliation: Department of Surgery, College of Medicine, University of Kentucky, Lexington, Kentucky40536, USA.
authors.forename: Changguo
authors.initials: C
authors.lastname: Chen
authors.forename: Hoonbae
authors.initials: H
authors.lastname: Jeon
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Johnston
authors.forename: Roberto
authors.initials: R
authors.lastname: Gedaly
authors.forename: Patrick P
authors.initials: PP
authors.lastname: McHugh
authors.forename: Dinesh
authors.initials: D
authors.lastname: Ranjan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects*; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008232:Lymphoproliferative Disorders / Q000139:chemically induced*; D008315:Malondialdehyde / Q000378:metabolism; D016377:Organ Transplantation / Q000009:adverse effects; D010084:Oxidation-Reduction; D011183:Postoperative Complications / Q000821:virology; D050050:Protein Carbonylation / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D011759:Pyrrolidines; D013859:Thiocarbamates; D014810:Vitamin E; C020972:pyrrolidine dithiocarbamic acid; D008315:Malondialdehyde; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D000111:Acetylcysteine