Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB

Srinivas SR, Prasad PD, Umapathy NS, Ganapathy V, Shekhawat PS. Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB . Am J Physiol Gastrointest Liver Physiol 293: G1046–G1053, 2007. First published September 13, 2007; doi:10.1152/ajpgi.00233.2007.—L-Carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter ATB . Loss-of-function mutations in OCTN2 may be associated with inflammatory bowel disease (IBD), suggesting a role for carnitine in intestinal/colonic health. In contrast, ATB is upregulated in bowel inflammation. Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. Butyryl-L-carnitine (BC), a butyrate ester of carnitine, may have potential for treatment of gut inflammation, since BC would supply both butyrate and carnitine. We examined the transport of BC via ATB to determine if this transporter could serve as a delivery system for BC. We also examined the transport of BC via OCTN2. Studies were done with cloned ATB and OCTN2 in heterologous expression systems. BC inhibited ATB -mediated glycine transport in mammalian cells (IC50, 4.6 0.7 mM). In Xenopus laevis oocytes expressing human ATB , BC induced Na -dependent inward currents under voltage-clamp conditions. The currents were saturable with a K0.5 of 1.4 0.1 mM. Na activation kinetics of BC-induced currents suggested involvement of two Na per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake (IC50, 1.5 0.3 M). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were Na dependent and saturable (K0.5, 0.40 0.02 M). We conclude that ATB is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. ATB may mediate intestinal absorption of BC when OCTN2 is defective.