Disease relevance of Slco1b2

• Multiple copies of the Oatp4 HNF1alpha response element, inserted upstream of a minimal promoter, were sufficient to mediate reporter activity and responded to the coexpression of HNF1alpha in mouse hepatoma cells [1].
• LST-1 and its polymorphism may be used as an additional marker of the TNF region, where genes responsible for autoimmune diseases are suspected to be localized [2].
• Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo [3].
• PVU II polymorphism of LST-1 (leucocyte specific transcript-1) in type I diabetes mellitus, Graves' disease and healthy controls [4].

Psychiatry related information on Slco1b2

• For the time-response study, LPS (5 mg/kg i.p.) produced a rapid decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice [5].

High impact information on Slco1b2

• Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected [6].
• Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice [7].
• In Hepa-1c1c7 cells, adenylyl cyclase activator forskolin as well as two cellular membrane-permeable cAMP analogs, dibutyryl cAMP and 8-bromo-cAMP, induced Oatp2 mRNA expression in a time- and dose-dependent manner [8].
• Luciferase activity driven by the Oatp2 promoter containing this CRE site was induced in cells cotransfected with a plasmid encoding the protein kinase A catalytic subunit [8].
• These three chemicals induced reporter gene activity in cells transfected with a luciferase reporter gene construct containing a 7.6-kilobase (kb) 5'-flanking region of mouse Oatp2 [8].

Biological context of Slco1b2

• The deduced amino acid sequence of the mouse lst-1 shares 64 and 77% identities with the reported human and rat lsts, respectively [9].
• The mouse lst-1 gene spans approximately 60 kbp in length and consists of 16 exons, including two noncoding exons [9].
• HNF1alpha bound to the Oatp4 HNF1 response element as a homodimer [1].
• Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter [1].
• The full-length rat lst-1 (designated rlst-1a) encodes a protein containing 687 amino acids and has 12-putative transmembrane domains, multiple potential N-glycosylation and phosphorylation sites [10].

Anatomical context of Slco1b2

• In cellular uptake studies using a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4), [(3)H]DHEAS uptake by TM-BBB4 cells exhibited a concentration dependence with a K:(m) of 34.4 microM: and was significantly inhibited by the oatp2-specific substrate digoxin [11].
• Organic anion transporting polypeptide 4 (Oatp4; Slc21a10) is expressed almost exclusively in liver, where it mediates uptake of a variety of compounds, including bile acids, as well as other endo- and xenobiotics, across hepatic sinusoidal membranes in a Na+-independent manner [12].

Associations of Slco1b2 with chemical compounds

• The peptidic delta opioid-receptor agonist [D-penicillamine(2,5)]-enkephalin (DPDPE) is a substrate of mdr1a P-gp and Oatp2 [13].
• PCN increased the hepatic uptake of [(3)H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO mice [3].
• Additionally, phenobarbital (PB)-inducible Oatp2 and Mrp3 gene expression was significantly increased in the PXR-KO mice when compared with wild-type PB-treated mice [14].
• In P-gp-deficient mice, DPDPE uptake was saturable (K(m) approximately 24 mM), and was inhibited by dexverapamil and the Oatp2 substrates digoxin, estradiol-17beta-glucuronide and fexofenadine [13].
• Lipopolysaccharide (LPS) has been shown to decrease Oatp4 mRNA levels in a dose- and time-dependent manner in Toll-like receptor 4 (TLR4)-normal (C3H/OuJ) mice, but not in TLR4-mutant (C3H/HeJ) mice [12].

Regulatory relationships of Slco1b2

• Thus, TLR4 is considered an upstream mediator of LPS-induced decrease in mouse Oatp4 mRNA [12].

Analytical, diagnostic and therapeutic context of Slco1b2

• Northern blot analysis demonstrates that mouse lst-1 mRNA is expressed exclusively in liver [9].
• In conclusion, DHEAS efflux transport takes place across the BBB, and studies involving in vitro DHEAS uptake and RT-PCR suggest that there is oatp2-mediated DHEAS transport at the BBB [11].
• RT-PCR and sequence analysis suggest that an oatp2 is expressed in TM-BBB4 cells [11].

References