Mycophenolate Mofetil

Bardsley-Elliot, Anne; Noble, Stuart; Foster, Rachel H.

doi:10.2165/00063030-199912050-00005

Cited by 35 publications

(3 citation statements)

References 141 publications

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“…11 It is the pro-drug of the active substance mycophenolic acid (MPA), which inhibits the de novo synthesis of guanosine nucleotides, resulting in selective inhibition of T- and B-cell proliferation. 4 …”

Section: Management Of High-risk Corneal Transplantationmentioning

confidence: 99%

Management of high-risk corneal transplantation

Zazzo

Kheirkhah

Abud

et al. 2017

Survey of Ophthalmology

124

102

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The cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal graft has high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates due to a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered. However, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been employed for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments as well as tolerance-inducing methods show promising horizons in the management of high-risk corneal transplantation in near future.

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Section: Management Of High-risk Corneal Transplantationmentioning

confidence: 99%

Management of high-risk corneal transplantation

Zazzo

Kheirkhah

Abud

et al. 2017

Survey of Ophthalmology

124

102

View full text Add to dashboard Cite

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“…The anti-proliferative drug mycophenolic acid (MPA) is a cornerstone of most immunosuppressive regimens after solid organ transplantation1. MPA exerts its immunosuppressive properties by inhibition of inosine 5′-monophosphate dehydrogenase (IMPDH), the enzyme that limits de novo purine synthesis.…”

mentioning

confidence: 99%

The Immunosuppressant Mycophenolic Acid Alters Nucleotide and Lipid Metabolism in an Intestinal Cell Model

Heischmann

Dzieciątkowska

Hansen

et al. 2017

Sci Rep

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The study objective was to elucidate the molecular mechanisms underlying the negative effects of mycophenolic acid (MPA) on human intestinal cells. Effects of MPA exposure and guanosine supplementation on nucleotide concentrations in LS180 cells were assessed using liquid chromatography-mass spectrometry. Proteomics analysis was carried out using stable isotope labeling by amino acids in cell culture combined with gel-based liquid chromatography-mass spectrometry and lipidome analysis using 1H nuclear magnetic resonance spectroscopy. Despite supplementation, depletion of guanosine nucleotides (p < 0.001 at 24 and 72 h; 5, 100, and 250 μM MPA) and upregulation of uridine and cytidine nucleotides (p < 0.001 at 24 h; 5 μM MPA) occurred after exposure to MPA. MPA significantly altered 35 proteins mainly related to nucleotide-dependent processes and lipid metabolism. Cross-reference with previous studies of MPA-associated protein changes widely corroborated these results, but showed differences that may be model- and/or method-dependent. MPA exposure increased intracellular concentrations of fatty acids, cholesterol, and phosphatidylcholine (p < 0.01 at 72 h; 100 μM MPA) which corresponded to the changes in lipid-metabolizing proteins. MPA affected intracellular nucleotide levels, nucleotide-dependent processes, expression of structural proteins, fatty acid and lipid metabolism in LS180 cells. These changes may compromise intestinal membrane integrity and contribute to gastrointestinal toxicity.

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“…MPA is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in de novo purine synthesis (18). Inhibition of IMPDH reduces synthesis of guanosine nucleotides, which are essential for DNA synthesis in T cells, resulting in reduced proliferation of T cells (19, 20). Despite the fact that the mechanism of action is largely known for these two drugs, it is not known whether their effect on cellular function involves epigenetic regulation, or whether they affect the epigenetic regulation of cytokine expression.…”

Section: Introductionmentioning

confidence: 99%

Interferon-Gamma DNA Methylation Is Affected by Mycophenolic Acid but Not by Tacrolimus after T-Cell Activation

et al. 2017

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Immunosuppressive drug therapy is required to treat patients with autoimmune disease and patients who have undergone organ transplantation. The main targets of the immunosuppressive drugs tacrolimus and mycophenolic acid (MPA; the active metabolite of mycophenolate mofetil) are T cells. It is currently unknown whether these immunosuppressive drugs have an effect on DNA methylation—an epigenetic regulator of cellular function. Here, we determined the effect of tacrolimus and MPA on DNA methylation of the gene promoter region of interferon gamma (IFNγ), a pro-inflammatory cytokine. Total T cells, naive T cells (CCR7+CD45RO−), and memory T cells (CD45RO+ and CCR7−CD45RO−) were isolated from CMV seropositive healthy controls and stimulated with α-CD3/CD28 in the presence or absence of tacrolimus or MPA. DNA methylation of the IFNγ promoter region was quantified by pyrosequencing at 4 h, days 1, 3, and 4 after stimulation. In parallel, T-cell differentiation, and IFNγ protein production were analyzed by flow cytometry at days 1 and 3 after stimulation. Our results show that MPA induced changes in IFNγ DNA methylation of naive T cells; MPA counteracted the decrease in methylation after stimulation. Tacrolimus did not affect IFNγ DNA methylation of naive T cells. In the memory T cells, both immunosuppressive drugs did not affect IFNγ DNA methylation. Differentiation of naive T cells into a central-memory-like phenotype (CD45RO+) was inhibited by both immunosuppressive drugs, while differentiation of memory T cells remained unaffected by both MPA and tacrolimus. IFNγ protein production was suppressed by tacrolimus. Our results demonstrate that MPA influenced IFNγ DNA methylation of naive T cells after stimulation of T cells, while tacrolimus had no effect. Both tacrolimus and MPA did not affect IFNγ DNA methylation of memory T cells.

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Mycophenolate Mofetil

Cited by 35 publications

References 141 publications

Management of high-risk corneal transplantation

Management of high-risk corneal transplantation

The Immunosuppressant Mycophenolic Acid Alters Nucleotide and Lipid Metabolism in an Intestinal Cell Model

Interferon-Gamma DNA Methylation Is Affected by Mycophenolic Acid but Not by Tacrolimus after T-Cell Activation

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