Involvement of organic anion transporting polypeptides in the toxicity of hydrophilic pravastatin and lipophilic fluvastatin in rat skeletal myofibres.
OBJECTIVE
There is a discrepancy in the adverse effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, statins between the clinical reports and the studies using skeletal muscle cell models. In the clinical reports, both hydrophilic and lipophilic statins induce myotoxicity, whereas in in vitro experiments using cell lines of myoblasts, lipophilic, but not hydrophilic, statins exert myotoxicity. We investigated the cause of this discrepancy.


METHODS
Skeletal myofibres, fibroblasts and satellite cells were isolated from rat flexor digitorum brevis (FDB) muscles. Using these primary cultured cells as well as the L6 myoblast cell line, we compared the toxicity of hydrophilic pravastatin and lipophilic fluvastatin. The mRNA expression levels of possible drug transporters for statins were also examined in these cells using reverse transcriptase-PCR.


RESULTS
In the skeletal myofibres, both pravastatin and fluvastatin induced vacuolation and cell death, whereas in the mononuclear cells only fluvastatin, but not pravastatin, was toxic. mRNA of the organic anion transporting polypeptides (Oatp) 1a4 and Oatp2b1 were expressed in the skeletal myofibres, but not in mononucleate cells. Estrone-3-sulphate, a substrate for Oatps, attenuated the effects of pravastatin and fluvastatin in skeletal myofibres; p-aminohippuric acid, a substrate for the organic anion transporters (Oats), but not Oatps, failed to do so.


CONCLUSIONS
The statin transporters Oatp1a4 and Oatp2b1 are expressed in rat skeletal myofibres, but not in satellite cells, fibroblasts or in L6 myoblasts. This is probably why hydrophilic pravastatin affects skeletal muscle, but not skeletal myoblasts.
Sakamoto
K
K
Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan. kazuho@fmu.ac.jp
Mikami
H
H
Kimura
J
J
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D000077340:Fluvastatin; D015870:Gene Expression; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity; D007211:Indoles / Q000633:toxicity*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D027361:Organic Anion Transporters / Q000187:drug effects / Q000378:metabolism*; D017035:Pravastatin / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D027361:Organic Anion Transporters; D017035:Pravastatin; D012333:RNA, Messenger; C503597:Slco1a4 protein, rat; C533062:Slco2b1 protein, rat