Sasaki Shotaro, Futagi Yuya, Ideno Masaya, Kobayashi Masaki, Narumi Katsuya, Furugen Ayako, Iseki Ken
Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
Department of Pharmacy, Hokkaido University Hospital, Sapporo 060-8648, Japan.
Eur J Pharmacol. 2016 Oct 5;788:248-254. doi: 10.1016/j.ejphar.2016.06.033. Epub 2016 Jun 21.
Solute carrier (SLC) 16A1 is a pH-dependent carrier of 5-oxoproline, a derivative of the amino acid. SLC16A1 interacts with carboxylate group-containing substrates, which are also present in atorvastatin, and might be the reason for its ability to interact with atorvastatin. Does atorvastatin interact with the carrier? Does it also interact with the carrier via the substrate recognition site? This study was carried out to answer these questions. Polymerase chain reaction was used to determine the expression of SLC16A1 in normal human astrocytes. We induced SLC16A1 expression in a mammalian cell line and in Xenopus laevis oocytes. We used [(3)H] 5-oxoproline for direct measurement of SLC16A1-specific transport activity. SLC16A1 was clearly observed in normal human astrocytes. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors inhibited the SLC16A1-specific transport of 5-oxoproline. Atorvastatin was the most potent inhibitor, with an inhibition constant of 40μM. The drug was a non-competitive inhibitor of SLC16A1. In the present study, we showed non-competitive inhibition of SLC16A1-specific transport activity by atorvastatin. However, the affinity between the drug and the carrier was extremely low. Therefore, the interaction of atorvastatin with SLC16A1 is unlikely to be a problem in clinical practice.
溶质载体（SLC）16A1是一种对pH敏感的5-氧代脯氨酸载体，5-氧代脯氨酸是一种氨基酸衍生物。SLC16A1与含羧基的底物相互作用，阿托伐他汀中也存在这些底物，这可能是其与阿托伐他汀相互作用的原因。阿托伐他汀是否与该载体相互作用？它是否也通过底物识别位点与该载体相互作用？开展本研究以回答这些问题。采用聚合酶链反应测定正常人星形胶质细胞中SLC16A1的表达。我们在哺乳动物细胞系和非洲爪蟾卵母细胞中诱导SLC16A1表达。我们使用[³H]5-氧代脯氨酸直接测量SLC16A1特异性转运活性。在正常人星形胶质细胞中清晰观察到SLC16A1。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂抑制5-氧代脯氨酸的SLC16A1特异性转运。阿托伐他汀是最有效的抑制剂，抑制常数为40μM。该药物是SLC16A1的非竞争性抑制剂。在本研究中，我们显示阿托伐他汀对SLC16A1特异性转运活性有非竞争性抑制作用。然而，该药物与载体之间的亲和力极低。因此，在临床实践中阿托伐他汀与SLC16A1的相互作用不太可能成为问题。
