Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter.
ABSTRACT We have demonstrated in the present study that novel organic cation transporter (OCTN) 2 is a transporter for organic cations as well as carnitine. OCTN2 transports organic cations without involving Na(+), but it transports carnitine only in the presence of Na(+). The ability to transport organic cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na(+) does not influence the affinity of OCTN2 for organic cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na(+)-independent organic cation transporter as well as a Na(+)-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
- SourceAvailable from: Frantisek Staud[Show abstract] [Hide abstract]
ABSTRACT: Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.Journal of Drug Targeting 09/2012; 20(9):736-63. DOI:10.3109/1061186X.2012.716847 · 2.72 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Former studies in rats demonstrated that starvation or treatment with the hypolipidemic drug clofibrate causes a marked increase in the concentration of carnitine in the liver. The molecular mechanisms underlying these phenomena in rats, however, have been largely unknown. Since both, fasting and clofibrate treatment lead to an activation of peroxisome proliferator-activated receptor alpha (PPARalpha), a ligand-activated transcription factor that acts as an important regulator of lipid metabolism and energy homeostasis, the hypothesis has been raised that activation of this nuclear receptor is responsible for the alterations in carnitine homeostasis observed in rodents by either stimulating carnitine uptake or carnitine biosynthesis or both of them. The present review summarizes recent evidence from studies with rodents and pigs supporting the hypothesis that activation of PPARalpha is responsible for the alterations in carnitine homeostasis previously observed. According to these novel results an essential role for PPARalpha in the regulation of carnitine uptake and carnitine biosynthesis in rodents and pigs has been clearly established. Due to the strong similarities in the gene response to PPARalpha agonists and the similar metabolic features and anatomic conditions between pigs and humans, it is likely that pharmacological PPARalpha agonists exert similar effects in humans.Pharmacological Research 10/2009; 60(3):179-84. DOI:10.1016/j.phrs.2009.01.016 · 3.98 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Identifying drug transporters and their in vivo significance will help to explain why some central nervous system (CNS) drugs cross the blood-brain barrier (BBB) and reach the brain parenchyma. We characterized the transport of the drug clonidine at the luminal BBB by in situ mouse brain perfusion. Clonidine influx was saturable, followed by Michaelis-Menten kinetics (K(m)=0.62 mmol/L, V(max)=1.76 nmol/sec per g at pH 7.40), and was insensitive to both sodium and trans-membrane potential. In vivo manipulation of intracellular and/or extracellular pH and trans-stimulation showed that clonidine was transported by an H+-coupled antiporter regulated by both proton and clonidine gradients, and that diphenhydramine was also a substrate. Organic cation transporters (Oct1-3), P-gp, and Bcrp did not alter clonidine transport at the BBB in knockout mice. Secondary or tertiary amine CNS compounds such as oxycodone, morphine, diacetylmorphine, methylenedioxyamphetamine (MDMA), cocaine, and nicotine inhibited clonidine transport. However, cationic compounds that interact with choline, Mate, Octn, and Pmat transporters did not. This suggests that clonidine is transported at the luminal mouse BBB by a new H+-coupled reversible antiporter.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2009; 29(7):1293-304. DOI:10.1038/jcbfm.2009.54 · 5.34 Impact Factor