Effects of music elements on mycophenolate glucuronidation in rat liver microsomes.
Adhiya Jinal J, Shalaby Ali H AH, Al-Dajani Ala'A R AR, El-Mahrouk Sara R SR et al.
Mycophenolic acid (MPA), a first-line immunosuppressant for preventing transplant organ rejection, exhibits substantial inter- and intra-individual pharmacokinetic variability. We hypothesized that music elements (tempo, rhythm, and harmony) can affect the formation of MPA glucuronide (the major, inactive metabolite, MPAG) and MPA acyl glucuronide (the minor, toxic metabolite, AcMPAG) in Sprague Dawley (SD) rats. SD rats (8-10 weeks; 200-300 g; N = 8 per group [equal sex]) were exposed for 24 h in a sound-monitored room with music combinations (fast or slow tempo with regular or irregular rhythm) versus controls. Liver microsomes were analysed for MPAG and AcMPAG formation under initial velocity conditions. As FT IR (fast tempo with irregular rhythm) significantly reduced AcMPAG formation, we further tested harmony (tonal vs. atonal [AH]) within FT IR using three independent composers and two published pieces. MPA glucuronides were quantified by liquid chromatography-tandem mass spectrometry. Enzyme kinetics in FT IR AH versus controls were determined across MPA concentrations (0-320 μg/mL). mRNA and protein expression of the AcMPAG-forming enzyme (UDP-glucuronosyltransferase UGT2B1) and other expressed UGTs were analysed. MPAG formation was unaffected by any music combination, whereas niflumic acid (100 μM, positive control) reduced it by ∼67%. AcMPAG formation was significantly reduced by FT IR (42.5 ± 14.4%; mean ± SEM; p < 0.05) and further reduced with added AH (74.4 ± 10.8%; p < 0.005). For MPAG, V max and CL int were comparable to controls, with a modestly higher K m . For AcMPAG, V max and CL int decreased by 89.7 ± 46.4% and 91.5 ± 29.7%, respectively (p < 0.05, n = 7 [3 males, 4 females]), with no change in K m . No sex differences in kinetic parameters were observed for either analyte. Inter-composer differences in MPA glucuronidation could be explained by the legato (continuous)-to-staccato (intermittent) articulation ratio. Hepatic Ugt2b1 mRNA and protein expression were unchanged after FT IR AH exposure, as were hepatic Ugt1a1, Ugt1a5, Ugt1a6, Ugt1a7, and Ugt2b12 mRNA. Our novel findings indicate that specific music elements (FT IR AH) reduced generation of the minor, toxic AcMPAG without affecting formation of the major, inactive MPAG. This is potentially therapeutically beneficial, as the adverse effects of MPA might be selectively attenuated without altering its clearance or therapeutic outcomes.