Ontogenic and longitudinal activity of Na⁺-nucleoside transporters in the human intestine

Abstract

The objectives of our study were to identify the types of nucleoside transporters present in the human fetal small intestine and to characterize their developmental activity, longitudinal distribution, and transport kinetics compared with those present in the adult intestine. Nucleoside uptake by intestinal brush-border membrane vesicles was measured by an inhibitor-stop rapid filtration technique. Only the purine-specific (N1; hCNT2) and the pyrimidine-specific (N2; hCNT1) Na(+)-dependent nucleoside transporters were found to be present on the brush-border membranes of the enterocytes along the entire length of the fetal and adult small intestines. The activity of these transporters was higher in the proximal than in the distal small intestine. Both the N1 and N2 transporters found in the fetal intestine shared similar kinetic properties (Michaelis-Menten constant and Na(+)-nucleoside stoichiometry) to those in the adult intestine. During the period of rapid morphogenesis (11-15 wk gestation), no temporal differences were apparent in the activity of the N1 and N2 transporters in the fetal small intestine. These findings have implications for the absorption of drugs from the amniotic fluid by the fetus after maternal drug administration of nucleoside drugs such as the antivirals zidovudine and didanosine.

Ribonucleic Acid Hydrolysis by Intestinal Explants of Neonatal Piglets

“…This may be because of the lower Km of Na + -concentrative nucleoside transporter CNT1 for uridine (59 mol/L) than for cytidine (140 mol/L), as observed in the human intestine (27). In addition, a partial transformation of cytidine into uridine mediated by adenosine deaminase cannot be excluded.…”

“…Some animal cells, including intestinal enterocytes, bone marrow, certain brain cells, erythrocytes, and leukocytes, are unable to synthesize purines de novo and thus must take up purines de- rived from dietary sources or from de novo synthesis by other cells, especially hepatocytes (26). It is now recognized that there are multiple carriers for the transport of nucleosides and nucleobases that function either by facilitated diffusion or Na + -cotransport (2,26,27). Thorell et al (18), using homogenates of fetal small intestine and human milk with and without added RNA, found CMP, UMP, and adenosine monophosphate, cytidine and uridine, hypoxhantine, xanthine, and uric acid after 4 hours of incubation.…”

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

“…The high abundance of CNTs in liver and renal tissues may contribute to the renal and hepatic toxicities observed when patients are treated with nucleoside analog drugs (Loewen et al, 1999). In the intestine, CNTs were localized by functional studies to brush border membranes (Chandrasena et al, 1997;Patil and Unadkat, 1997;Ngo et al, 2001), whereas ENTs were localized to basolateral membranes (Chandrasena et al, 1997;Lum et al, 2000). There is a wide variation in the expression of hCNT1 mRNA in normal kidney in different individuals (Pennycooke et al, 2001) and relatively low levels of expression of hCNT1 mRNA in tumor samples (Pennycooke et al, 2001).…”

Functional Characterization of a Nucleoside-Derived Drug Transporter Variant (hCNT3C602R) Showing Altered Sodium-Binding Capacity

“…There are two families of nucleoside carriers in mammalian cells, the equilibrative ENT/SLC29A transporters, with low affinity and wide selectivity, and the concentrative CNT/SLC28A transporters, with higher affinity and more restricted selectivity (Griffith and Jarvis, 1996;Baldwin et al, 1999). Because absorptive cells in the renal and intestinal epithelia express all members of the concentrative CNT family (Gutierrez and Giacomini, 1993;Ngo et al, 2001;Rodríguez-Mulero et al, 2005;Errasti-Murugarren et al, 2007), any change in their activity might be highly relevant in the pharmacokinetics of nucleoside-derived drugs.…”