Bakar, Nur Salwani and Kamali, Farhad and A. Brown, Colin D
(2016)
Effect of Statins on Functional Expression of
Membrane Transporters in L6 Rat Skeletal
Muscle Cells.
J. of Biomed. & Clin. Sci, 1 (1).
pp. 17-26.
Abstract
Statins reduce LDL-cholesterol and the risk of
atherosclerosis. They are generally safe, although statin-induced myopathy is
relatively common. Membrane transporters play a crucial role in determining
statin side effects. Little is known regarding the interaction of drug transporters
in muscle cells with statins. Study aims: The present study aimed to determine
the effect of statins on functional expression of monocarboxylate transporters
(MCTs) and multidrug resistance-associated proteins (MRPs) in L6 rat
skeletal myotube cells. Methods: Relative gene expression at mRNA level
was confirmed by RT2 ProfilerTM Rat Drug Transporter PCR array. The uptake
of 3H-labelled DL-lactate (1 μCi/ml) was measured to functionally expressed
MCT function. The inhibition of [3H]-DL-lactate uptake was assessed in the
presence or absence of statins and compared to that of the MCT inhibitors,
phloretin and CHC. Transporter-mediated dye efflux was used as functional
assay for the MRP efflux transporters. Results: In L6 rat skeletal myotubes,
relatively high mRNA expression level was observed for Mct1and Mrp1for
uptake and efflux transporters, respectively. The [3H]-DL-lactate uptake was
shown to be a concentration-, pH-dependent and Na+-independent manner
with Michaelis-Menten constant (Km) value of 16.17 ± 2.4 mM vs 15.63 ± 3.0
mM in the presence and absence of Na+, respectively. The maximum velocity
of substrate binding (Vmax) of the DL-lactate uptake inhibition by lipophilic
statins; simvastatin and atorvastatin, were in the same order as phloretin and
CHC, while no significant inhibitory magnitude with hydrophilic statins;
pravastatin and rosuvastatin. However, the L6 rat skeletal myotubes did not
exhibit lactate efflux function. Among four of statins used, only simvastatin
showed an affinity inhibition of MRP function in L6 cells. Conclusions: This
study has shown that lipophilic statins significantly inhibit functional
expression of MCTs, even though they have not shown relatively high
inhibition impact on MRPs.
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