Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
In target safety assessment that identifies toxicological concerns for a pharmacological target, information on the phenotype of animals with a modified gene encoding the target is very useful. However, in the case that on-target toxicity to an inhibitor/antagonist is predicted using information on knockout animals, it should be noted that there are two different loss-of-function modes. Generally, the phenotype observed in knockout animals is expressed upon the irreversible and constitutive deletion of the gene encoding the target from the embryonic development stage. On the other hand, the on-target-based phenotype by the inhibitor/antagonist is expressed by reversible and time/concentration-dependent binding between the target and the inhibitor/antagonist during a specific period after birth. It is suggested that this difference in the loss-of-function mode may lead to a difference in adaptive responses, which may ultimately lead to a difference in phenotype. Therefore, we do not judge the validity of a pharmacological target only by the phenotype observed in genetically modified animals, but always judge it based on the results of toxicity tests using an inhibitor/antagonist with appropriate pharmacological activity.
Genetically modified animals and gene-knockdown cultured cells are also useful in determining whether the observed toxicity is based on on-target or off-target effects. It is expected that sharing and discussing our application of gene-modified animals or cultured cells in our presentation would support efficient new drug development in the future.
