Title Pharmacological and pathophysiological roles of carnitine / organic

The carnitine/organic cation transporter (OCTN) family consists of three transporter isoforms, i.e., OCTN1 (SLC22A4) and OCTN2 (SLC22A5) in humans and animals and Octn3 (Slc22a21) in mice. These transporters are physiologically essential to maintain appropriate systemic and tissue concentrations of carnitine by regulating its membrane transport during intestinal absorption, tissue distribution, and renal reabsorption. Among them, OCTN2 is a sodium-dependent, high-affinity transporter of carnitine, and functional defect of OCTN2 due to genetic mutation causes primary systemic carnitine deficiency (SCD). Since carnitine is essential for beta-oxidation of long-chain fatty acids to produce ATP, OCTN2 gene mutation causes a range of symptoms, including cardiomyopathy, skeletal muscle weakness, fatty liver, and male infertility. These functional consequences of Octn2 gene mutation can be clearly seen in an animal model, jvs mouse, which exhibits the SCD phenotype. In addition, although the mechanism is not clear, single nucleotide polymorphisms of OCTN1 and OCTN2 genes are associated with increased incidences of rheumatoid arthritis, Crohn’s disease and asthma. OCTN1 and OCTN2 accept cationic drugs as substrates and contribute to intestinal and pulmonary absorption, tissue distribution (including to tumor cells), and renal excretion of these drugs. Modulation of the transport activity of OCTN2 by externally administered drugs may cause drug-induced secondary carnitine deficiency. Octn3 transports carnitine specifically, particularly in male reproductive tissues. Thus, the OCTNs are physiologically, pathologically and pharmacologically important. Detailed characterization of these transporters will greatly improve our understanding of the pathology associated with common diseases caused by functional deficiency of OCTNs.