Effect of the antioxidant idebenone on adverse events under mycophenolate mofetil therapy in a rat model.
BACKGROUND
Diarrhea and anemia are side effects of mycophenolic acid (MPA), but underlying mechanisms are not fully understood. Gene expression of major-alpha-hemoglobin and catalase was suppressed in livers of mycophenolate mofetil (MMF)-treated rats, suggesting MPA attenuates cellular defense against reactive oxygen species (ROS). We investigated whether the antioxidant idebenone might alleviate MPA-related side effects.


METHODS
Rats were treated as follows: group 1: controls; group 2: idebenone; group 3: MMF; and group 4: MMF/idebenone. Blood was collected weekly to determine cell counts, hemoglobin, MPA, plasma albumin, total protein, creatinine, and urea concentrations. On day 28 RNA was extracted from liver, kidneys, and bone marrow (BM). Colon and jejunum were examined histologically.


RESULTS
High-dose MMF-treated rats developed diarrhea, dehydration, and weight loss. After a week, a significant decrease (P=0.001) in erythrocyte count and hemoglobin concentration was observed that was not influenced by idebenone. Degenerative changes in the jejunum were slightly attenuated by idebenone. Idebenone did not influence MPA-induced suppression of catalase. A significant suppression of major-alpha-hemoglobin and the erythropoietin (EPO)-receptor in BM of MMF-treated groups and almost complete absence of hemopoietic progenitor cells were observed. EPO-mRNA was markedly upregulated in the MMF-group and even more in the MMF/idebenone-group.


CONCLUSIONS
Idebenone showed minimal benefit on MMF-related diarrhea and anemia. BM of MMF-treated rats revealed erythroid aplasia as a possible reason for anemia. Marked upregulation of EPO-mRNA presumably reflects a compensatory mechanism. Because ROS have the potential to suppress EPO expression, it can be hypothesized that enhanced EPO-mRNA expression in MMF/idebenone-treated rats is caused by antagonism of ROS.
Heller
Tanja
T
Abteilung Klinische Chemie, Georg-August-Universität, 37075 Göttingen, Germany. hellertanja@web.de
Geide
Anna
A
Bonitz
Ulrike
U
Wegner
Ulrike
U
Gröne
Hermann-Josef
HJ
Armstrong
Victor W
VW
Oellerich
Michael
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000235:genetics; D003106:Colon / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D004921:Erythropoietin / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006454:Hemoglobins / Q000235:genetics; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007583:Jejunum / Q000473:pathology; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D017467:Receptors, Erythropoietin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D018076:DNA, Complementary; D006454:Hemoglobins; D007166:Immunosuppressive Agents; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D014451:Ubiquinone; D002374:Catalase; C036619:idebenone; D009173:Mycophenolic Acid