Basolateral Efflux Transporters: A Potentially Important Pathway for the Prevention of Cholestatic Hepatotoxicity

JacksonJonathan, P; FreemanKimberly, M; FrileyWeslyn, W; L.Iii, St. ClaireRobert; BlackChris,; BrouwerKenneth, R

doi:10.1089/aivt.2016.0023

Cited by 27 publications

(42 citation statements)

References 29 publications

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“…These data suggest that the increase in the basolateral efflux is much greater than the increase in the apical efflux, consistent with results for CDCA treated SCHH (Jackson et al. ). A follow‐up study of mechanistic modeling and simulation will be to evaluate the extent of BSEP‐mediated apical efflux, and OST α /OST β ‐mediated basolateral efflux after OCA treated SCHH.…”

Section: Discussionsupporting

confidence: 91%

“…), thus allowing natural bile acids and bile acid analogues to efflux into bile pockets and reduce intracellular accumulation and cytotoxicities (Jackson et al. ).…”

Section: Discussionmentioning

confidence: 99%

“…This in vitro technique preserves the in vivo ‐like bile acid biosynthesis and regulatory pathways (Jackson et al. ) including uptake and efflux transporters proper localization (Hoffmaster et al. ; Li et al.…”

Section: Introductionmentioning

confidence: 99%

“…This was accomplished by utilizing sandwich-cultured human hepatocytes (SCHH). This in vitro technique preserves the in vivo-like bile acid biosynthesis and regulatory pathways (Jackson et al 2016) including uptake and efflux transporters proper localization (Hoffmaster et al 2004;Li et al 2009). SCHH are also capable of determining hepatobiliary distribution of endogenous bile acids (Swift et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich‐cultured human hepatocytes

Zhang

Jackson

Claire

et al. 2017

Pharmacology Res & Perspec

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Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100‐fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich‐cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose‐dependently increased fibroblast growth factor‐19 (FGF‐19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7‐alpha‐hydroxylase (CYP7A1), the rate‐limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8‐fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OST α) and OST β increased by 6.4 ± 0.2‐fold and 42.9 ± 7.9‐fold, respectively. The upregulation of BSEP and OST α and OST β, by OCA reduced the intracellular concentrations of d8‐TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid‐induced toxicity observed in cholestatic diseases.

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Section: Discussionsupporting

confidence: 91%

“…), thus allowing natural bile acids and bile acid analogues to efflux into bile pockets and reduce intracellular accumulation and cytotoxicities (Jackson et al. ).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich‐cultured human hepatocytes

Zhang

Jackson

Claire

et al. 2017

Pharmacology Res & Perspec

Self Cite

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show abstract

“…Several liver transporter genes exhibited altered expression, in particular the efflux p-glycoprotein transporter ABCB1 (DCF, APAP, DTL, CBZ), the cannicular organic anion transporter 1 and 2, ABCC2 and ABCC3 , (APAP, MMI, TBF, CBZ and ETM), the organic solute transporter gene OSTβ (DCF, APAP, ETM), the organic anion transporter SLCO1A2 (DCF, MMI, CBZ), and the sodium-bile acid co-transporter SLC10A1 (APAP, TBF). The perturbation of several transporter genes indicates that the tissue is ramping up the export of bile acids and solutes to prevent cholestatic hepatotoxicity [73]. …”

Section: Discussionmentioning

confidence: 99%

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

Vickers¹,

Ulyanov

Fisher³

2017

IJMS

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Drugs with clinical adverse effects are compared in an ex vivo 3-dimensional multi-cellular human liver slice model. Functional markers of oxidative stress and mitochondrial function, glutathione GSH and ATP levels, were affected by acetaminophen (APAP, 1 mM), diclofenac (DCF, 1 mM) and etomoxir (ETM, 100 µM). Drugs targeting mitochondria more than GSH were dantrolene (DTL, 10 µM) and cyclosporin A (CSA, 10 µM), while GSH was affected more than ATP by methimazole (MMI, 500 µM), terbinafine (TBF, 100 µM), and carbamazepine (CBZ 100 µM). Oxidative stress genes were affected by TBF (18%), CBZ, APAP, and ETM (12%-11%), and mitochondrial genes were altered by CBZ, APAP, MMI, and ETM (8%-6%). Apoptosis genes were affected by DCF (14%), while apoptosis plus necrosis were altered by APAP and ETM (15%). Activation of oxidative stress, mitochondrial energy, heat shock, ER stress, apoptosis, necrosis, DNA damage, immune and inflammation genes ranked CSA (75%), ETM (66%), DCF, TBF, MMI (61%-60%), APAP, CBZ (57%-56%), and DTL (48%). Gene changes in fatty acid metabolism, cholestasis, immune and inflammation were affected by DTL (51%), CBZ and ETM (44%-43%), APAP and DCF (40%-38%), MMI, TBF and CSA (37%-35%). This model advances multiple dosing in a human ex vivo model, plus functional markers and gene profile markers of drug induced human liver side-effects.

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An Introduction to DILIsym® Software, a Mechanistic Mathematical Representation of Drug-Induced Liver Injury

Battista

Howell²,

Siler³

et al. 2018

Methods in Pharmacology and Toxicology

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Basolateral Efflux Transporters: A Potentially Important Pathway for the Prevention of Cholestatic Hepatotoxicity

Cited by 27 publications

References 29 publications

Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich‐cultured human hepatocytes

Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich‐cultured human hepatocytes

Liver Effects of Clinical Drugs Differentiated in Human Liver Slices

An Introduction to DILIsym® Software, a Mechanistic Mathematical Representation of Drug-Induced Liver Injury

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