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Figure 1. Expression of Mac-1 and l-selectin on neutrophils stimulated with control and pancreatitis serum. Severe necrotizing pancreatitis was induced by intraductal infusion of <t>glycodeoxycholic</t> acid (GDOC) combined with supramaximal cerulein infusion. Leukocytes were labeled with fluorescein isothiocyanate-labeled monoclonal CD11b (Mac-1 α chain) or CD62L (l-selectin) antibody. Mean fluorescence intensity of the gated neutrophil population, identified by characteristic forward- and side-scatter profile, was measured on a FACScan flow cytometer. * P = .02, †P = .006 vs. control.
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Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: <t>glycodeoxycholate</t> sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.
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Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: <t>glycodeoxycholate</t> sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.
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Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: <t>glycodeoxycholate</t> sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.
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Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: <t>glycodeoxycholate</t> sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.
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Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: <t>glycodeoxycholate</t> sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.
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Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: <t>glycodeoxycholate</t> sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.
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Figure 1. Expression of Mac-1 and l-selectin on neutrophils stimulated with control and pancreatitis serum. Severe necrotizing pancreatitis was induced by intraductal infusion of glycodeoxycholic acid (GDOC) combined with supramaximal cerulein infusion. Leukocytes were labeled with fluorescein isothiocyanate-labeled monoclonal CD11b (Mac-1 α chain) or CD62L (l-selectin) antibody. Mean fluorescence intensity of the gated neutrophil population, identified by characteristic forward- and side-scatter profile, was measured on a FACScan flow cytometer. * P = .02, †P = .006 vs. control.

Journal:

Article Title: Expression of the Adhesion Molecules Mac-1 and l-Selectin on Neutrophils in Acute Pancreatitis is Protease- and Complement-Dependent

doi:

Figure Lengend Snippet: Figure 1. Expression of Mac-1 and l-selectin on neutrophils stimulated with control and pancreatitis serum. Severe necrotizing pancreatitis was induced by intraductal infusion of glycodeoxycholic acid (GDOC) combined with supramaximal cerulein infusion. Leukocytes were labeled with fluorescein isothiocyanate-labeled monoclonal CD11b (Mac-1 α chain) or CD62L (l-selectin) antibody. Mean fluorescence intensity of the gated neutrophil population, identified by characteristic forward- and side-scatter profile, was measured on a FACScan flow cytometer. * P = .02, †P = .006 vs. control.

Article Snippet: Glycodeoxycholic acid (GDOC, Sigma Chemical Co.) in glycylglycine-NaOH buffered solution (pH 8.0, room temperature) was infused retrogradely into the biliopancreatic duct at a concentration of 10 mmol/L in a volume (1.2 mL/kg)-, time (10 minutes)-, and pressure (30 mmHg)-controlled fashion, followed by intravenous infusion of cerulein (5 μg/kg/h, Takus, Farmitalia, Carlo Erba GmBH, Freiburg, Germany) for 6 hours.

Techniques: Expressing, Labeling, Fluorescence, Flow Cytometry

Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: glycodeoxycholate sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.

Journal: Clinical pharmacology and therapeutics

Article Title: Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1

doi: 10.1002/cpt.434

Figure Lengend Snippet: Twelve metabolites (i to xii) significantly associated with OATP1B1-Val174Ala in both a genomewide association study of human metabolites11 and significantly associated in healthy volunteers receiving pravastatin and cyclosporine, an OATP1B1 inhibitor. a. Manhattan plots of the 12 metabolites. Manhattan plots were generated using the publicly available data, which provided the meta-analysis p-values of each SNP (http://mips.helmholtz-muenchen.de/proj/GWAS/gwas/index.php?task=download). The large green circle represents the OATP1B1 functional variant, Val174Ala (rs4149056). Other loci which include genes for transporters or enzymes are labeled. OATP1B1-Val174Ala or its LD variant (r2>0.8) is significantly associated with eight metabolites with the strongest p-values in the GWAS (metabolites (i) - (vii) and (ix)). b. The 12 metabolites significantly higher in healthy volunteers after administration of cyclosporine (CSA) compared to placebo (P). Each dot represents the metabolite intensity in the plasma from an individual after administration of placebo (P) or cyclosporine (CSA) and each line connects the metabolite intensity from the same individual following placebo or CSA administration. The color of the line represents the genotype of OATP1B1-Val174Ala, where blue represents homozygous reference allele, green represents heterozygous reference allele and red represents homozygous reduced function variant. The p-values of the paired t-test between the placebo and CSA treatment group are shown in the figure. Individuals with the variant for OATP1B1-Val174Ala (after placebo administration) had significantly higher metabolites levels of X-11529, X-13429, TDA, HDA and X-11905 (p<0.005). The mean and SD for each of the 12 metabolites in each genotype group are shown in Supplemental Table 5. Note: X-11529: Glycochenodeoxycholate glucuronide; X-13429: glycodeoxycholate sulfate or isomer; TDA: Tetradecanedioate; HDA: Hexadecanedioate; X-11905: Unknown; X-14626: Unknown; 4-Andros.: 4-androsten-3-beta,17-beta-diol disulfate 2*; ODA: Octadecanedioate; TLS: Taurolithocholate 3-sulfate; X-11440: Unknown; X-12850: Glycochenodeoxycholate sulfate or isomer; 1,5-AG: 1,5-anhydroglucitol.

Article Snippet: Tetradecanedioic acid, hexadecanedioic acid, taurolitocholate-3-sulfate, glycochenodeoxycholate, glycodeoxycholate and 1,5-anhydroglucitol were purchased from Sigma-Aldrich (St. Louis, MO).

Techniques: Generated, Functional Assay, Variant Assay, Labeling

Twelve candidate metabolites, which are significantly associated with higher levels in subjects with minor allele C for rs4149056 (OATP1B1-Val174Ala) with p <0.05 and also significantly associated with higher levels in healthy volunteers (20 participants) after dosing with cyclosporine (CSA) with q <0.2.

Journal: Clinical pharmacology and therapeutics

Article Title: Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1

doi: 10.1002/cpt.434

Figure Lengend Snippet: Twelve candidate metabolites, which are significantly associated with higher levels in subjects with minor allele C for rs4149056 (OATP1B1-Val174Ala) with p <0.05 and also significantly associated with higher levels in healthy volunteers (20 participants) after dosing with cyclosporine (CSA) with q <0.2.

Article Snippet: Tetradecanedioic acid, hexadecanedioic acid, taurolitocholate-3-sulfate, glycochenodeoxycholate, glycodeoxycholate and 1,5-anhydroglucitol were purchased from Sigma-Aldrich (St. Louis, MO).

Techniques:

Inhibitor effect on 11 transporters using transfected cell lines or membrane vesicles from transfected cell lines. Metabolites were tested as inhibitors at 30 μM. The colors indicate the different range of inhibition by the metabolites. Since the publication of Shin et al. 2014 10 , a few previously unknown compounds have been identified by Metablon Inc., X-11529, X-13429 and X-12850, which are likely to be glycochenodeoxycholate glucuronide,  glycodeoxycholate  sulfate and glycochenodexycholate sulfate, respectively.

Journal: Clinical pharmacology and therapeutics

Article Title: Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1

doi: 10.1002/cpt.434

Figure Lengend Snippet: Inhibitor effect on 11 transporters using transfected cell lines or membrane vesicles from transfected cell lines. Metabolites were tested as inhibitors at 30 μM. The colors indicate the different range of inhibition by the metabolites. Since the publication of Shin et al. 2014 10 , a few previously unknown compounds have been identified by Metablon Inc., X-11529, X-13429 and X-12850, which are likely to be glycochenodeoxycholate glucuronide, glycodeoxycholate sulfate and glycochenodexycholate sulfate, respectively.

Article Snippet: Tetradecanedioic acid, hexadecanedioic acid, taurolitocholate-3-sulfate, glycochenodeoxycholate, glycodeoxycholate and 1,5-anhydroglucitol were purchased from Sigma-Aldrich (St. Louis, MO).

Techniques: Transfection, Inhibition

Bile acid profiles in the GI tract (duodenum, ileum, cecum, and rectum) of control rats

Journal: The FASEB Journal

Article Title: Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption

doi: 10.1096/fj.13-231860

Figure Lengend Snippet: Bile acid profiles in the GI tract (duodenum, ileum, cecum, and rectum) of control rats

Article Snippet: Chemicals and reagents Lithocholate (LCA), nordeoxycholate (NDCA), murideoxycholate (MDCA), hyodeoxycholate (HDCA), chenodeoxycholate (CDCA), deoxycholate (DCA), dehydrocholate (DHCA), glycocholate (GCA), taurolithocholate (TLCA), glycolithocholate (GLCA), α-muricholate (α-MCA), β-muricholate (β-MCA), ω-muricholate (ω-MCA), λ-muricholate (λ-MCA), cholate (CA), 7-dehydrocholate (7-DCA), methyl deoxycholate (methyl DCA), 6,7-diketodeoxycholate (6,7-DKDCA), tauro α-muricholate (T α-MCA), tauro β-muricholate (T β-MCA), taurocholate (TCA), tauroursodeoxycholate (TUDCA), taurohyodeoxycholate (THDCA), taurochenodeoxycholate (TCDCA), taurodeoxycholate (TDCA), glycoursodeoxycholate (GUDCA), glycohyodeoxycholate (GHDCA), glycochenodeoxycholate (GCDCA), glycodeoxycholate (GDCA), cholate-d4 (CA-d4; 5β-cholanic acid-3α,7α,12α-triol-2,2,4,4-d4), glycocholate-d4 (GCA-d4; 5β-cholanic acid-3α,7α,12α-triol N -(carboxymethyl)-amide-2,2,4,4-d4), lithocholate-d4 (LCA-d4; 5β-cholanic acid-3α-ol-2,2,4,4-d4), and deoxycholate-d4 (DCA-d4; 5β-cholanic acid-3α, 12α-diol-2,2,4,4-d4) were purchased from Steraloids, Inc. (Newport, RI, USA).

Techniques: Control