Submitted on May 23, 2007
Accepted on September 10, 2007
Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB0,+
Srinivas R. Sonne1, Puttur D Prasad2, Nagavedi S Umapathy3, Vadivel Ganapathy3, and Prem S Shekhawat4*
1 Pediatrics, Medical College of Georgia, Augusta, Georgia, United States
2 Med Coll Georgia; Biochemistry & Molecular Biology, Med Coll Georgia, Augusta, Georgia, United States
3 Biochemistry & Molecular Biology, Medical College of Georgia, Augusta, Georgia, United States
4 Pediatrics, Biochemistry & Molecular Biology, Medical College of Georgia, Augusta, Georgia, United States
* To whom correspondence should be addressed. E-mail: pshekhawat{at}mail.mcg.edu.
L-Carnitine is absorbed in the intestinal tract via carnitine transporter OCTN2 and amino acid transporter ATB0,+. 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, ATB0,+ is up-regulated 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 as BC would supply both butyrate and carnitine. We examined the transport of BC via ATB0,+ 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 ATB0,+ and OCTN2 in heterologous expression systems. BC inhibited ATB0,+-mediated glycine transport in mammalian cells (IC50, 4.6 ± 0.7 mM). In X. laevis oocytes expressing human ATB0,+, 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 2 Na+ per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake (IC50, 1.5 ± 0.3 µM). 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 µM). We conclude that ATB0,+ is a low-affinity/high-capacity transporter for BC whereas OCTN2 is a high-affinity/low-capacity transporter. ATB0,+ may mediate intestinal absorption of BC when OCTN2 is defective.
