Influence of mycophenolic acid and tacrolimus on homocysteine metabolism

Background. The effect of mycophenolate mofetil (MMF) on homocysteine (Hcy) metabolism is unknown. Methods. This in vitro study examined whether mycophenolic acid or tacrolimus influences the formation of Hey as determined by measuring the total Hey (tHcy) concentrations in supernatants of human renal proximal tubule epithelial cells. Cells were incubated with and without vitamins (folate, vitamin B-6 and B-12) in the presence of low or high methionine concentrations at different mycophenolic acid (0, or 5, or 20 mug/mL) or tacrolimus (0, or 10, or 25 ng/mL) concentrations for 241 48 or 72 hours. The concentration of tHcy in culture supernatants was measured by a fluorescence polarization immunoassay. The effect of MMF on tHcy plasma levels was also examined in 454 kidney graft recipients. Results. Comparisons of tHcv levels in culture supernatants over time by four way ANOVA, showed that methionine concentration (P < 0.00001), time (P < 0.00001), vitamins (P = 0.002728), and mycophenolic acid concentration (P = 0.000095) were all significant predictors of tHcy concentrations. This was due to significantly lower tHcy levels with using mycophenolic acid at a high concentration versus control at the 48 and 72-hour time points. By contrast, tacrolimus showed no effect in vitro. Among the kidney graft recipients, male patients on MMF therapy showed lower plasma tHcy concentrations as compared to those on azathioprine (P = 0.03). Conclusion, Our study suggests a tHcy lowering effect of MMF in male transplant recipients, which improves the cardiovascular disease risk profile, whereas tacrolimus showed no effect.