title: 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.affiliation: Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Sonne R
authors.initials: SR
authors.lastname: Srinivas
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Nagavedi S
authors.initials: NS
authors.lastname: Umapathy
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Prem S
authors.initials: PS
authors.lastname: Shekhawat
mesh_terms: D026924:Amino Acid Transport System A / Q000502:physiology; D026905:Amino Acid Transport Systems / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D002331:Carnitine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D005260:Female; D005998:Glycine / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D010920:Placenta; D011247:Pregnancy; D011355:Prodrugs / Q000493:pharmacokinetics
chemical_list: D026924:Amino Acid Transport System A; D026905:Amino Acid Transport Systems; D027701:Organic Cation Transport Proteins; D011355:Prodrugs; C467737:SLC22A16 protein, human; C427065:butyrylcarnitine; D002331:Carnitine; D005998:Glycine