Induction of cytokine release by the acyl glucuronide of mycophenolic acid: A link to side effects?

Objectives: We have identified an acyl glucuronide (M-2) of the immunosuppr essant mycophenolic acid (MPA). Acyl glucuronides have toxic potential and may contribute to drug toxicity. Whether acyl glucuronides are able to indu ce release of proinflammatory cytokines is unknown. Gastrointestinal distur bances have been observed during MPA therapy and may involve an inflammator y reaction. This study investigated whether M-2 can induce IL-6 and TNF-alp ha release as well as gene expression of these cytokines in leukocytes. Design and 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. Expressio n 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 MP AG were without effect. Cytokine liberation depended on mRNA induction. Res ponse 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 mediat e some of the toxic actions of MPA. Copyright (C) 2000 The Canadian Society of Clinical Chemists.