Developing and characterizing a mouse model of hepatotoxicity using oral pyrrolizidine alkaloid (monocrotaline) administration, with potentiation of the liver injury by co-administration of LPS

Abstract

Oral administration of xenobiotics is preferable for research in in vivo models because it mimics the real life situation of human subjects. Therefore, oral (po) monocrotaline (MCT) (a common contaminant of dietary supplements)/intraperitoneal (ip) lipopolysaccharides (LPS)-induced liver injury possibly imitates idiosyncratic hepatotoxicity in humans. Cytokines, for example interleukin-1β (IL-1β) and transforming growth factor beta (TGF-β) are known to play a role in the development of toxicity and repair processes, respectively. The purpose of this study was to develop and characterize a model of po MCT/ip LPS hepatotoxicity which may elucidate the mechanisms of injury. ND4 male mice were given MCT (200 mg/kg) followed 4 h later by LPS (6 mg/kg). Blood samples were drawn for plasma chemistry and IL-1β. Animals were euthanized and livers were harvested at different time points. We have shown that MCT/LPS cotreatment results in significant elevation of plasma alanine aminotransferase (ALT), CRP, IL-1β and TGF-β. Histopathological evaluation revealed diffuse degenerative injury. In summary, we have established a reproducible in vivo model of hepatotoxicity by po MCT/ip LPS cotreatment that may closely mimic real life idiosyncratic hepatotoxicity.