scholarly journals Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Metabolites ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 282
Author(s):  
Cristina Gómez ◽  
Simon Stücheli ◽  
Denise V. Kratschmar ◽  
Jamal Bouitbir ◽  
Alex Odermatt
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Bile Acids ◽  
Liver Tissue ◽  
Bioactive Molecules ◽  
Rodent Species ◽  
Drug Induced ◽  
Tissue Samples ◽  
Drug Induced Liver Injury ◽  
Bile Acid Profiles

Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

scholarly journals Bile acids in drug induced liver injury: Key players and surrogate markers

2016 ◽  
Vol 40 (3) ◽  
pp. 257-266 ◽  
Author(s):  
Heiko S. Schadt ◽  
Armin Wolf ◽  
Francois Pognan ◽  
Salah-Dine Chibout ◽  
Michael Merz ◽  
...  
Keyword(s):  
Liver Injury ◽  
Bile Acids ◽  
Surrogate Markers ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Key Players

scholarly journals Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

2017 ◽  
pp. kfx018 ◽  
Author(s):  
Francis S. Wolenski ◽  
Andy Z. X. Zhu ◽  
Mike Johnson ◽  
Shaoxia Yu ◽  
Yuu Moriya ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Evaluation of 3-D bioprinted human liver tissue for assessment drug-induced liver injury across a diverse set of chemical classes

2017 ◽  
Vol 280 ◽  
pp. S270
Author(s):  
Jeffrey Irelan ◽  
Candace Crogan-Grundy ◽  
Ryan Smith ◽  
Rhiannon Hardwick ◽  
Deborah Nguyen
Keyword(s):  
Liver Injury ◽  
Liver Tissue ◽  
Human Liver ◽  
Drug Induced ◽  
Human Liver Tissue ◽  
Drug Induced Liver Injury

Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

2013 ◽  
Vol 268 (1) ◽  
pp. 79-89 ◽  
Author(s):  
Makoto Yamazaki ◽  
Manami Miyake ◽  
Hiroko Sato ◽  
Naoya Masutomi ◽  
Naohisa Tsutsui ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury

2018 ◽  
Vol 314 (5) ◽  
pp. G597-G609 ◽  
Author(s):  
Melina M. Malinen ◽  
Izna Ali ◽  
Jacqueline Bezençon ◽  
James J. Beaudoin ◽  
Kim L. R. Brouwer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Tissue ◽  
Primary Biliary Cholangitis ◽  
Drug Induced ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

The heteromeric steroid transporter organic solute transporter α/β (OSTα/β, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OSTα/β. Based on observations first reported here that hepatic OSTα/β is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTα/β function and interaction with drugs and bile acids. OSTα/β expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTα/β-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OSTα/β-mediated transport was evaluated. Expression of OSTα/β was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTα/β was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTα/β-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTα/β inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OSTα/β-overexpressing cells. Our findings demonstrate that OSTα/β is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OSTα/β is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTα/β substrates exhibit rapid, linear, and concentration-driven transport in an OSTα/β-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTα/β-mediated taurocholate transport. These data suggest that hepatic OSTα/β plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

scholarly journals Auriculatone Sulfate Effectively Protects Mice Against Acetaminophen-Induced Liver Injury

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3642
Author(s):  
Liangcai Lin ◽  
Huanyu Guan ◽  
Rui Li ◽  
Xiangming Liao ◽  
Feifei Zhao ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Tissue ◽  
Water Solubility ◽  
Immunohistochemical Analysis ◽  
Western World ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Tnf Α ◽  
Histological Results ◽  
Human Liver Disease

Acetaminophen (APAP) overdose is very common worldwide and has been widely recognized as the leading cause of drug-induced liver injury in the Western world. In our previous investigation, auriculatone, a natural product firstly obtained from Aster auriculatus, has demonstrated a potent protective effect against APAP-induced hepatotoxicity in HL-7702 cells. However, the poor water solubility and low bioavailability restrict its application. Auriculatone sulfate (AS) is a sulfated derivative of auriculatone with highly improved water-solubility. Hepatoprotective effects against APAP-induced liver injury (AILI) showed that intragastric pretreatment with AS at 50 mg/kg almost completely prevented mice against APAP-induced increases of serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and ATPase. Histological results showed that AS could protect the liver tissue damage. In addition, AS pretreatment not only significantly retained hepatic malondialdehyde and the activities of glutathione, superoxide dismutase, and glutathione peroxidase at normal levels, but also markedly suppressed the increase of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels in mouse liver caused by overdose APAP. Immunohistochemical analysis showed that AS obviously attenuated the expression of CD45 and HNE in liver tissue. Further mechanisms of action investigation showed that inhibition of cytochrome P450 3A11 (CYP 3A11) and CYP2E1 enzymatic activities (but not that of CYP1A2) was responsible for APAP bioactivation. In conclusion, AS showed a hepatoprotective effect against AILI through alleviating oxidative stress and inflammation and inhibiting CYP-mediated APAP bioactivation. It may be an effective hepatoprotective agent for AILI and other forms of human liver disease.

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