Induction of cytokine release by the acyl glucuronide of mycophenolic acid: a link to side effects?
OBJECTIVE
We have identified an acyl glucuronide (M-2) of the immunosuppressant mycophenolic acid (MPA). Acyl glucuronides have toxic potential and may contribute to drug toxicity. Whether acyl glucuronides are able to induce release of proinflammatory cytokines is unknown. Gastrointestinal disturbances have been observed during MPA therapy and may involve an inflammatory reaction. This study investigated whether M-2 can induce IL-6 and TNF-alpha release as well as gene expression of these cytokines in leukocytes.


METHODS
M-2 was produced by incubation of MPA with human liver microsomes. Human mononuclear leukocytes were incubated in the presence of M-2. Concentrations of IL-6 and TNF-alpha were measured by ELISA. Expression of mRNA was determined by quantitative RT-PCR.


RESULTS
Incubation of 3 x 10(6) cells with M-2 resulted in a time and dose dependent release of cytokines, whereas MPA or its phenolic glucuronide MPAG were without effect. Cytokine liberation depended on mRNA induction. Response to M-2 showed much inter individual variability (30-fold for IL-6, 3-fold for TNF-alpha).


CONCLUSIONS
If M-2 promotes release of cytokines in vivo, these may mediate some of the toxic actions of MPA.
Wieland
E
E
Abteilung Klinische Chemie, Georg-August-Universität Göttingen, Göttingen, Germany. ewieland@med.uni-goettingen.de
Shipkova
M
M
Schellhaas
U
U
Schütz
E
E
Niedmann
P D
PD
Armstrong
V W
VW
Oellerich
M
M
D000328:Adult; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005965:Glucuronates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020719:Glucuronides; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008862:Microsomes, Liver / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D005965:Glucuronates; D020719:Glucuronides; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; C113145:mycophenolic acid glucuronide; D003513:Cycloheximide; D009173:Mycophenolic Acid