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.
"C, Nicotine uptake was measured at 37 °C for 10 s with increasing concentrations of nicotine. [ choline (a substrate of the choline transport system) (Allen and Smith, 2001), L-carnitine (an OCTN2 substrate) (Wu et al., 1999), and p-aminohippurate (a substrate of organic anion transporter (OAT) (VanWert et al., 2010)) had little effect. Eadie–Scatchard plot analysis of the concentration-dependent [ 3 H]nicotine uptake by TR-BBB13 cells with 50 lM pyrilamine (Fig. 5), showed that the plots of [ 3 H]nicotine uptake in the absence (closed circles) and presence (open squares) of pyrilamine intersected at the horizontal axis. "
[Show abstract][Hide abstract] ABSTRACT: Nicotine is the most potent neural pharmacological alkaloid in tobacco, and the modulation of nicotine concentration in the brain is important for smoking cessation therapy. The purpose of this study was to elucidate the net flux of nicotine transport across the blood-brain barrier (BBB) and the major contributor to nicotine transport in the BBB. The in vivo brain-to-blood clearance was determined by a combination of the rat brain efflux index method and a rat brain slice uptake study, and the blood-to-brain transport of nicotine was evaluated by in vivo vascular injection in rats and a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB13 cells) as an in vitro model of the rat BBB. The blood-to-brain nicotine influx clearance was obtained by integration plot analysis as 272 μL/(min•g brain), and this value was twofold greater than the brain-to-blood efflux clearance (137 μL/(min•g brain)). Thus, it is suggested that the net flux of nicotine transport across the BBB is dominated by blood-to-brain influx transport. In vivo blood-to-brain nicotine transport was inhibited by pyrilamine. [(3)H]Nicotine uptake by TR-BBB13 cells exhibited time-, temperature-, and concentration-dependence with a K(m) value of 92 μM. Pyrilamine competitively inhibited nicotine uptake by TR-BBB13 cells with a K(i) value of 15 μM, whereas substrates and inhibitors of organic cation transporters had little effect. These results suggest that pyrilamine-sensitive organic cation transport process(es) mediate blood-to-brain influx transport of nicotine at the BBB, and this is expected to play an important role in regulating nicotine-induced neural responses.
Neurochemistry International 12/2012; 62(2). DOI:10.1016/j.neuint.2012.11.014 · 3.09 Impact Factor
"DRG appears to express some transporters involved in the uptake of platinum derivatives (see the following), such as copper transporter 1 , electroneutral organic cation transporters 1 and 2 (OCTN1, and OCTN2) . However, these transporters are also expressed in the brain neurons [57–59]. At my knowledge, there is no information on the expression of multidrug and toxin extrusion protein 1 and of organic cation transporters in DRGs. "
[Show abstract][Hide abstract] ABSTRACT: Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1), the copper transporter 2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2), and the multidrug extrusion transporter 1 (MATE1). Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.
"transfer of carnitine from mother to fetus; supply of carnitine to the placenta for its own metabolic needs quinidine, valproic acid, verapamil, cephaloridine (Wu et al., 1999; Shekhawat et al., 2003; Lahjouji et al., 2004; Grube et al., 2005; Klaassen and Aleksunes, 2010) OAT4 SLC22A11 basolateral H transport of sulfoconjugated estrogens; uptake of precursors for placental de novo synthesis of estrogens zidovudine, valproic acid, tetracycline (Cha et al., 2000; Takeda et al., 2002; Ugele et al., 2003; Yamashita et al., 2006; Ugele et al., 2008; "
[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 · 2.74 Impact Factor
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