Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver

Abstract

-It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Druginduced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity. In this study, we examined whether chimeric mice can reveal species differences in DIPL. Changes in various phosphatidylcholine (PhC) molecules were investigated in the liver of chimeric mice after administering amiodarone, which induces phospholipidosis. Liquid chromatography-tandem mass spectrometry revealed that levels of PhCs tended to increase in the liver after administration of amiodarone. The liver of chimeric mice consists of human hepatocytes and residual mouse hepatocytes. We used imaging mass spectrometry (IMS) to evaluate the increase of PhCs in human and mouse hepatocytes after administration of amiodarone. IMS visualizes localization of endogenous and exogenous molecules in tissues. The IMS analysis suggested that the localized levels of several PhCs tended to be higher in the human hepatocytes than those in mouse hepatocytes, and PhC levels changed in response to amiodarone. Chimeric mice with a humanized liver will be useful to evaluate species differences in DIPL between mice and humans.

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

“…Accordingly, numerous studies revealed the administration of troglitazone, amiodarone, and bosentan, which are indicated for type 2 diabetes, arrhythmia, and pulmonary hypertension, respectively, resulted in the generation of human-specific reactive metabolites in the liver of HLCM, which led to the development of liver injury. 60,[272][273][274][275] Of important note, emerging evidence revealed that for most, but not all, the occurrence of DILI results from the activation of the adaptive immune response. 69 Genomewide association studies demonstrated a strong association between HLA typing and the occurrence of DILI.…”

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

“…16) Another study reported that rifampicin (clinical dose; 900 mg) significantly increases human serum bile acid concentrations. 17) These compounds are also known to exert inhibitory effects on BSEP and are associated with related hepatotoxicity in humans. 4) In the present study, we used ketoconazole and rifampicin as model compounds.…”

Changes in Bile Acid Concentrations in Chimeric Mice Transplanted with Different Replacement Indexes of Human Hepatocytes

“…For example, it is known that HBV infects chimeric mice with both low and high RIs; however, HCV does not infect chimeric mice with a low RI. 6) To elucidate the effects of species differences in the metabolic profiles of mice and humans, Sanoh et al 9) used mass spectrometry imaging to report changes occurring in the phosphatidylcholines localized in the human and mouse regions in the liver of chimeric mice with a medium RI. By using chimeric mice with low, medium and high RIs respectively, Kitamura et al 10) and Sanoh et al 7) demonstrated the effects of aldehyde oxidase and cytochrome P450 (CYP) metabolism on the remaining mouse hepatocytes.…”