OBJECTIVES: 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. 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. 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.
OBJECTIVES: 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. 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. 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 glucuronideMPAG 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.
Authors: Jean-Baptiste Woillard; Nicolas Picard; Antoine Thierry; Guy Touchard; Pierre Marquet Journal: Pharmacogenet Genomics Date: 2014-05 Impact factor: 2.089
Authors: Michel Mourad; Pierre Wallemacq; Josiane König; Evelyne Henry de Frahan; Djamila Chaib Eddour; Martine De Meyer; Jacques Malaise; Jean Paul Squifflet Journal: Clin Pharmacokinet Date: 2002 Impact factor: 6.447
Authors: Charles D Varnell; Tsuyoshi Fukuda; Cassie L Kirby; Lisa J Martin; Barry L Warshaw; Hiren P Patel; Deepa H Chand; Gina-Marie Barletta; Scott K Van Why; Rene G VanDeVoorde; Donald J Weaver; Amy Wilson; Priya S Verghese; Alexander A Vinks; Larry A Greenbaum; Jens Goebel; David K Hooper Journal: Pediatr Transplant Date: 2017-09-04