Changes in Bile Acid Concentrations after Administration of Ketoconazole or Rifampicin to Chimeric Mice with Humanized Liver

Abstract

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis. In the present study, we used chimeric mice with humanized liver as a model to study druginduced cholestasis. Administration of a single dose of ketoconazole or rifampicin, known to potentially cause cholestasis by inhibiting BSEP, did not result in elevated levels of alkaline phosphatase (ALP), which are known hepatic biomarkers. The concentration of taurodeoxycholic acid increased in the liver after ketoconazole administration, whereas rifampicin resulted in increased tauromuricholic acid and taurocholic acid (TCA) levels in the liver and plasma. Furthermore, rifampicin resulted in an increase in the uniform distribution of a compound with m/z 514.3, presumed as TCA through imaging mass spectrometry. The mRNA levels of bile acid-related genes were also altered after treatment with ketoconazole or rifampicin. We believe these observations to be a part of a feedback mechanism to decrease bile acid concentrations. The changes in bile acid concentrations results may reflect the initial responses of the human body to cholestasis. Furthermore, these findings may contribute to the screening of drug candidates, thereby avoiding drug-induced cholestasis during clinical trials and drug development.

Understanding Idiosyncratic Toxicity: Lessons Learned from Drug-Induced Liver Injury

“…Several studies have reported minor elevations in ALT or bile acid in response to IDILI drugs in mice with humanized livers, suggesting that this model is sufficient to replicate the early steps that proceed an adaptive immune attack and more significant liver injury. , A particularly impressive humanized liver model is derived from the NOG mouse expressing a thymidine kinase transgene (TK-NOG). A recent study in TK-NOG mice demonstrated both a humanized profile of biliary excretion as well as cholestatic liver injury after 1 week of treatment with bosentan .…”

Screening of Biomarkers and Toxicity Mechanisms of Rifampicin-Induced Liver Injury Based on Targeted Bile Acid Metabolomics

“…The reason for the increase in ALT activity is also correlated with skeletal muscle, cardiac injury or metabolic state, except for histopathology change (Zhao et al, 2017). Moreover, a previous study found that the levels of hepatic and serum BAs and BA-related genes increase notably, with no elevation in serum ALT, AST, and alkaline phosphatase levels after administering a dose of RIF (Sanoh et al, 2019). Another study showed that the levels of serum conjugated BAs [glycocholic acid (GCA) and taurocholic acid (TCA)] increase in the rats with bile duct hyperplasia without significant changes in ALT and AST levels (Slopianka et al, 2017).…”

Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review

“…Cholesterol 7α hydroxylase (CYP7A1) is a rate-limiting enzyme in bile acid synthesis in hepatocytes. Its activity is regulated by the negative feedback of the farnesoid X receptor/small heterodimer partner (FXR/SHP) pathway ( Sanoh et al, 2019 ). There was evidence ( Xu et al, 2016 ) that RFP suppresses the FXR/SHP pathway, increases CYP7A1 mRNA expression, and promotes bile acid synthesis in hepatocytes.…”