Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+).

Abstract

L-carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). 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(0,+) 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(0,+) 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(0,+) and OCTN2 in heterologous expression systems. BC inhibited ATB(0,+)-mediated glycine transport in mammalian cells (IC(50), 4.6 +/- 0.7 mM). In Xenopus laevis oocytes expressing human ATB(0,+), BC induced Na(+) -dependent inward currents under voltage-clamp conditions. The currents were saturable with a K(0.5) 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 (IC(50), 1.5 +/- 0.3 microM). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were Na(+) dependent and saturable (K(0.5), 0.40 +/- 0.02 microM). We conclude that ATB(0,+) is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. ATB(0,+) may mediate intestinal absorption of BC when OCTN2 is defective.

• Authors: Sonne R Srinivas, Puttur D Prasad, Nagavedi S Umapathy, Vadivel Ganapathy, Prem S Shekhawat
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 293 Issue 5 Pg. G1046-53 (Nov 2007) ISSN: 0193-1857 [Print] United States
• PMID: 17855766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acid Transport System A
• Amino Acid Transport Systems
• Organic Cation Transport Proteins
• Prodrugs
• SLC22A16 protein, human
• butyrylcarnitine
• Carnitine
• Glycine

Topics

• Amino Acid Transport System A (physiology)
• Amino Acid Transport Systems (physiology)
• Biological Transport (drug effects)
• Carnitine (analogs & derivatives, pharmacokinetics, pharmacology)
• Cell Line
• Cloning, Molecular
• Female
• Glycine (metabolism)
• Humans
• Kinetics
• Oocytes (drug effects, physiology)
• Organic Cation Transport Proteins (physiology)
• Placenta
• Pregnancy
• Prodrugs (pharmacokinetics)