Abstract
Drug-induced liver injury (DILI) is a major cause of withdrawal after marketing, so it is necessary to evaluate DILI risk. Mitochondrial toxicity is one of the crucial factors for predicting DILI, and several methods have been established. Although these methods have been widely used due to their high throughput, this does not deny the importance of another mitochondrial toxicity mechanism. Among them, we have focused on mitochondrial membrane permeability transition (MPT), common to drugs that cause severe DILI. While our research has only focused on hepatocytes, we try to evaluate the effects of MPT on inflammatory cells. When acetaminophen was administered to mice that lack a component of MPT in bone marrow-derived cells, we confirmed that acetaminophen-induced liver injury could be involved in the MPT in platelets. MPT has not been actively evaluated because its contribution to liver injury is unclear, and isolated mitochondria from the organs of experimental animals are required for evaluation. Regarding this point, when MPT is induced in platelets, different activation occurs compared to the general activation process; we try to construct an alternative method to conventional MPT evaluation by using platelet activation. Furthermore, there are species differences in the difficulty of predicting liver injury. Species differences mean not only differences between humans and animals but also between experimental animals, so selecting an appropriate animal species is crucial depending on the purpose of the experiments. We have also investigated species differences between animals using lipopolysaccharide, which can induce MPT in rats and mice.
