The murine cationic amino acid transporter 1 (mCAT1) protein mediates membrane transports of L-arginine, L-lysine, L-histidine, and L-ornithine. The importance of mCAT1-mediated transport was underscored by the phenotype of mCAT1 gene-knockout mice, which exhibit anemia. 1) In addition, we reported that L-arginine that is a substrate of CAT1 is essential for the differentiation to erythrocyte by in vitro cell culture study.2) It has been also observed that L-arginine deficiency affects maturation of early B cells in the bone marrow, but not development of the T cells in the thymus. 3)However, the detailed biological role of the L-arginine in proliferation and differentiation of blood cells and K562 cells that are human leukemia cell line is not clear. L-Arginine is the precursor of polyamines, nitric oxide (NO), and agmatine that are associated with cell proliferation and differentiation.4) While NO can induce an apoptosis of megakaryocytes and a formation of platelet, 5,6) it was reported that NO inhibited differentiation of K562 cells. 7) L-Ornithine is produced by arginase and further metabolized into polyamines such as putrescine, spermidine and spermine, which regulate the cell cycle.8) Moreover, there is some evidence that agmatine acts as an antiproliferative molecule through induction of the protein antizyme.9) Antizyme inhibits ornithine decarboxylase (ODC), hence polyamine biosynthesis. At the same time, antizyme suppresses polyamine uptake. Based on these reports, it was considered that polyamines might be metabolic products of L-arginine that can facilitate differentiation of hematopoietic precursors to erythrocytes.Polyamines (putrescine, spermidine and spermine) play a crucial role in regulating gene expression, signal transduction, ion channel function, DNA and protein synthesis, as well as cell proliferation and differentiation.10) The intracellular polyamine concentration in human erythrocytes is reported to be relatively high; putrescine 0.6 mM (males), and 0.9 mM (females); spermidine 18 and 24 mM; spermine 19 and 15 mM. 11) Polyamines are also scavengers of reactive oxygen species, thereby protecting DNA, protein, and lipids from oxidative damage.12) Available evidence shows that polyamines are key regulators of angiogenesis, early mammalian embryogenesis, placental trophoblast growth, and embryonic development.13) The cellular polyamines are thought to be supplied through de novo synthesis from L-arginine and transport, while the mammalian polyamine transporter gene has not been identified, 14,15) unlike bacterial and/or fungal polyamine transporter. 10,16) De novo polyamine synthesis is governed in part by the activity of ornithine decarboxylase (ODC), which catalyzes the conversion of the amino acid, L-ornithine to the diamine and putrescine. When the ODC activity was inhibited by alpha-difluoromethylornithine (DFMO) in K562 cells, proliferation of K562 cells was inhibited through abolishment of intracellular polyamines.17) It was also reported that spermine induced hemoglobin production i...
The tissue distribution and disposition of carnitine, which plays an important role in the transport of longchain fatty acids across the mitochondrial inner membrane for b b-oxidation, are well controlled by carnitine transporter organic cation/carnitine transporter 2 (OCTN2). Since little information is available on regulation of the expression of the OCTN2 gene, we examined the factors that affect the expression level of rat Octn2 (rOctn2), focusing on nuclear receptor peroxisome proliferator activated receptor alpha (PPARa a), which regulates expression of genes associated with b b-oxidation of fatty acids. mRNA of rOctn2 was induced by the PPARa a ligand fenofibrate in primary-cultured rat hepatocytes. Further, the PPARa a ligand Wy14643 increased the expression of Octn2 in wild-type mice, but not in PPARa a knockout mice. Analysis of the rOctn2 promoter region suggested the presence of putative cis elements of PPARa a. Wistar rats treated with intraperitoneal fenofibrate administration showed increased expression of rOctn2 mRNA in liver, and uptake of [ 3 H]carnitine by freshly isolated hepatocytes derived from those rats was also increased. In conclusion, our results indicate that the nuclear receptor PPARa a directly up-regulates the expression of rOctn2 and increases the hepatic uptake of carnitine via rOctn2.
Both influx and efflux transporters are thought to be involved in the intestinal absorption of fexofenadine. The present study examined the influx transporter-mediated intestinal absorption of fexofenadine in rats, focusing on the role of rat oatp3 (Oatp1a5). The intestinal permeability of fexofenadine was evaluated by means of the Ussing chamber method in the presence of a P-glycoprotein inhibitor to block efflux transport. The permeability of fexofenadine from the mucosal to the serosal side was higher than that from the serosal side to the mucosal side. Transport of fexofenadine was saturable, and was significantly decreased by an organic anion transporting polypeptide (oatp) inhibitor. Furthermore, uptake of fexofenadine by Xenopus oocytes expressing rat oatp3 was significantly greater than that by water-injected oocytes, and the affinity of oatp3 for fexofenadine (Km) was about 60 microM, which is comparable with the value obtained by the Ussing chamber method using rat intestinal tissues. These results indicate that oatp3 plays a role as an influx transporter in the intestinal absorption of fexofenadine in rats.
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