Interaction of β-lactam antibiotics with the mitochondrial carnitine/acylcarnitine transporter

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• 作者：Lorena Pochini ; Michele Galluccio ; Domenica Scumaci ; Nicola Giangregorio ; Annamaria Tonazzi ; Ferdin ; o Palmieri ; Cesare Indiveri
• 关键词：β ; -Lactams ; Carnitine ; Transport ; Mitochondria
• 刊名：Chemico-Biological Interactions
• 出版年：2008
• 出版时间：17 June 2008
• 年：2008
• 卷：173
• 期：3
• 页码：187-194
• 全文大小：600 K

文摘

The interaction of β-lactams with the purified mitochondrial carnitine/acylcarnitine transporter reconstituted in liposomes has been studied. Cefonicid, cefazolin, cephalotin, ampicillin, piperacillin externally added to the proteoliposomes, inhibited the carnitine/carnitine antiport catalysed by the reconstituted transporter. The most effective inhibitors were cefonicid and ampicillin with IC₅₀ of 6.8 and 7.6 mM, respectively. The other inhibitors exhibited IC₅₀ values above 36 mM. Kinetic analysis performed with cefonicid and ampicillin revealed that the inhibition is completely competitive, i.e., the inhibitors interact with the substrate binding site. The Ki of the transporter is 4.9 mM for cefonicid and 9.9 mM for ampicillin. Cefonicid inhibited the transporter also on its internal side. The IC₅₀ was 12.9 mM indicating that the inhibition was less pronounced than on the external side. Ampicillin and the other inhibitors were much less effective on the internal side. The β-lactams were not transported by the carnitine/acylcarnitine transporter. Cephalosporins, and at much lower extent penicillins, caused irreversible inhibition of the transporter after prolonged time of incubation. The most effective among the tested antibiotics was cefonicid with IC₅₀ of 0.12 mM after 60 h of incubation. The possible in vivo implications of the interaction of the β-lactam antibiotics with the transporter are discussed.