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Pendred Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SLC26A4 (solute carrier family 26 member 4, or human pendrin polypeptide) gene on chromosome 7q22.3 spans 67 kb and encodes a 780 aa, 85 kDa anion transporter protein (pendrin) belonging to the SLC26 anion transporter family.
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Research done in the 1960s with isolated bovine chromaffin granules have identified a vesicular transporter, originally named chromaffin granule amine transporter (CGAT). This transporter was later identified as VMAT1, and is now classified as solute carrier family 18 member 1 (SLC18A1). The VMAT1 gene (SLC18A1) is located on human chromosome 8p21.3, while the VMAT2 gene (SLC18A2) is located on chromosome 10q25. Studies using cultures of chromaffin cells and sympathetic ganglia indicated that increased stimulation and calcium influx up-regulate VMAT transcription, while only minimal changes in gene expression were seen in vivo in response to VMAT inhibition by various drugs. As is the case for other integral membrane proteins, the vesicular transporters are synthesized in the ER and are posttranslationally modified in the ER and Golgi, where they also undergo N-linked glycosylation.
ABC Transporters, Organic Solute Carriers and Drug Metabolising Enzymes in Bile Duct Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Members of the solute carrier family of proteins are located at the sinusoidal or basolateral domain of the hepatocyte surface. They mediate the uptake of solutes from blood to liver (Fig. 1). Table 1 shows an overview of human solute carriers expressed in liver. Structurally, the amino acid sequences of solute carrier proteins from rats and mice differ considerably from humans. Functionally, solute carriers show a considerable overlap in substrate specificity. In view of this apparent redundancy of uptake transporters one may question what the relevant transporter is for a given substrate under normal conditions. This not only depends on the level of expression of a given transport-protein but also on their mode of action. For example, NTCP, the sodium dependent bile salt transporting protein, is driven by a downhill sodium gradient from plasma to hepatocyte, thus allowing transport of bile salts from blood to liver.7 Under normal conditions NTCP is the major bile salt transporter. However, when the free bile salt concentration in blood exceeds that in hepatocytes, some of the sodium independent OATPs can also act as bile salt uptake transporters.8–10 On the other hand, when the intrahepatic bile salt concentration exceeds that of blood, as may occur in cholestasis, OATPs may act as sinusoidal effluxers.
Direct antiviral agents (DAAs) and their use in pregnant women with hepatitis C (HCV)
Published in Expert Review of Anti-infective Therapy, 2022
Sandra Abdul Massih, Ahizechukwu C. Eke
Placental drug transporters can greatly impact drug disposition during pregnancy. Not only does this affect the drug, but it also puts the fetus at risk for drugs that have teratogenic effects [59]. The most extensively studied placental drug transporters belong to the solute carrier family (SLC) and the ABC protein family [60]. As many DAAs are substrates of these drug transporters, diffusion through the placental membranes has been reported. For instance, SOF, VEL, VPR, LDV, and GLE are substrates of the placental efflux transporter P-gp [34,36,40]. As P-gp is one of the efflux transporters localized in the placenta, it could potentially affect trans-placental transport of DAAs [60]. In a recent in-vitro study by Pfeifer et al. [61], placental P-gp and BCRP expression increased in HCV positive women. It is expected that placental efflux transporter P-gp would potentially help limit the fetal exposure [61], but more pregnancy studies are needed.
Compound heterozygous mutations in the SLC4A11 gene associated with congenital hereditary endothelial dystrophy in a Chinese family
Published in Ophthalmic Genetics, 2022
Min Liu, Jia-Li Xia, Hong Yang, Ling Yu
Congenital inherited endothelial dystrophy (CHED) is a rare genetic disorder, which is clinically characterized by corneal turbidity and stromal layer edema caused by corneal endothelial dysfunction (1). The symptoms presenting at birth or within the first few years of life may slowly alleviate over the next few years (2). Subsequently, this disease may lead to nystagmus and significant impairment of vision. Many cases have been reported in consanguineous families, suggesting that CHED may be inherited as an autosomal recessive disease. Patients with CHED have specific corneal histopathologic changes, including diffuse corneal epithelial and stromal edema, loss of Bowman’s membrane, thickening of the retroelastic membrane, and abnormal morphology of the endothelial cells (3). Previously, CHED was divided into autosomal recessive (CHED2) and autosomal dominant (CHED1). In 2015, Weiss et al. developed a new IC3D classification of corneal dystrophies based on new clinical, histopathological, and genetic information. CHED1 mainly manifested as posterior polymorphous corneal dystrophy (PPCD) and was excluded from the diagnosis (4). Genetic linkage analysis showed that CHED was caused by homozygous or compound heterozygous mutations of the solute carrier family 4 member 11(SLC4A11) gene 610206, (5), which encodes a sodium borate cotransporter on chromosome 20p13. The SLC4A11 gene codes for BTR1, which is essential for cellular boron homeostasis, cell growth, and proliferation (6). To date, more than 100 mutations of SLC4A11 have been reported, of which approximately 94 mutations are related to CHED (7).
The chlorophenoxy herbicide MCPA: a mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs
Published in Xenobiotica, 2022
Alex Gledhill, Rachael Bowen, Michael Bartels, Andrew Bond, Git Chung, Colin Brown, Keith Pye, Tarang Vora
Based on structure, MCPA is considered to be a substrate for the renal organic anion transport (OAT) system. The OAT transporters form part of the Solute Carrier Family 22 (SLC22), selected members of which are expressed in the proximal tubule of the kidney but are also found in many other tissues including the liver. As indicated by their name, the OATs are involved in the renal clearance of water soluble, negatively charged organic compounds. The major OATs involved with renal transport are OAT1 and OAT3 with expression levels of OAT2 being somewhat lower (Eraly et al. 2004; Burckhardt 2012). The importance of OAT4 is less well understood. There is some substrate specificity overlap apparent between OAT1 and OAT3 (Eraly et al. 2004; VanWert et al. 2010). The OATs are polyspecific and thus substrates include both endogenous products and xenobiotics. It is relevant to note that glycine conjugates are substrates for OAT transporters, PAH (para-aminohippuric acid) the classical substrate for organic anion secretory pathways in the proximal tubule is itself a glycine conjugate. Although the OATs generally are thought to facilitate the renal excretion of substrates, the location of some of these transporters in the apical membrane indicates some involvement in the re-uptake of substrates from the lumen of the proximal tubule.