The metabolic fate of fenclozic acid in chimeric mice with a humanized liver

Abstract

The metabolic fate of the human hepatotoxin fenclozic acid ([2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetic acid) (Myalex) was studied in normal and bile-cannulated chimeric mice with a humanized liver, following oral administration of 10 mg/kg. This in vivo animal model was investigated to assess its utility to study “human” metabolism of fenclozic acid, and in particular to explore the formation of electrophilic reactive metabolites (RMs), potentially unique to humans. Metabolism was extensive, particularly involving the carboxylic acid-containing side chain. Metabolism resulted in the formation of a large number of metabolites and involved biotransformation via both oxidative and conjugative routes. The oxidative metabolites detected included a variety of hydroxylations as well as cysteinyl-, N-acetylcysteinyl-, and cysteinylglycine metabolites. The latter resulted from the formation of glutathione adducts/conjugates providing evidence for the production of RMs. The production of other classes of RMs included acyl-glucuronides, and the biosynthesis of acyl carnitine, taurine, glutamine, and glycine conjugates via potentially reactive acyl-CoA intermediates was also demonstrated. A number of unique “human” metabolites, e.g., those providing evidence for side-chain extension, were detected in the plasma and excreta of the chimeric liver-humanized mice that were not previously characterised in, e.g., the excreta of rat and C57BL/6 mice. The different pattern of metabolism seen in these chimeric mice with a humanized liver compared to the conventional rodents may offer clues to the factors that contributed to the drug-induced liver injury seen in humans.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2274-0) contains supplementary material, which is available to authorized users.

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

“…As mentioned above, TEM analyses reassured the formation of bile canaliculi in between xenotransplanted hepatocyte, which then networks to the intrahepatic bile ductules, namely Canals of Herring, followed by further connections to the intrahepatic bile duct. 52,59,60 Consequently, the composition of human hepatocytes-derived bile acid in the gall bladder of HLCM shows a positive correlation to the degree of RI. 61 This structural and functional re-establishment of the bile excretion machinery is particularly important for the in vivo study of xenobiotic metabolism, as the physiological biliary excretion system is an essential route for the elimination of drug metabolites.…”

Advancements in stem cell-derived hepatocyte-like cell models for hepatotoxicity testing

“…The authors found a dose-dependent liver toxicity in chimeric mice with a humanized liver as compared with non-humanized mice. Although currently most chimeric mice with humanized liver models used in hepatotoxicity testing (including the works of Kakuni et al and Xu et al mentioned above) were generated by transplanting PHHs [ 133 – 135 ], the use of stem cells to serve as hepatocyte sources for chimeric mice with a humanized liver is promising because stem cells are easily obtained and can be large-scale produced [ 136 ] (Fig. 1 ).…”

Highlight report: New applications of chimeric mice with humanized livers

“…It has been reported that humanized mouse livers show some features of human gene expression patterns and mirror responses of human liver to hepatotoxic drugs (Go 2018). In a recent issue of the Archives of Toxicology, Anja Ekdahl and colleagues used chimeric mice with humanized livers to study the metabolism of fenclozic acid (Ekdahl et al 2018). Fenclozic acid was developed as an alternative to high-dose therapy with aspirin (Chalmers et al 1969a, b).…”

“…Fenclozic acid was developed as an alternative to high-dose therapy with aspirin (Chalmers et al 1969a, b). Although fenclozic acid showed a good safety profile in experimental animals, it had to be withdrawn from late-stage clinical development because of hepatotoxicity (Ekdahl et al 2018;Alcock 1970;Hart et al 1970). The study was performed following oral administration of 10 mg fenclozic acid per kg body weight in bile-cannulated humanized mice (Ekdahl et al 2018).…”

“…Although fenclozic acid showed a good safety profile in experimental animals, it had to be withdrawn from late-stage clinical development because of hepatotoxicity (Ekdahl et al 2018;Alcock 1970;Hart et al 1970). The study was performed following oral administration of 10 mg fenclozic acid per kg body weight in bile-cannulated humanized mice (Ekdahl et al 2018). Interestingly, the authors were able to detect human-specific metabolites, such as fenclozic acid with side-chain extension in plasma and excreta, and could establish differences in metabolic patterns compared to conventional mice.…”