PhD conferral Yongjie Zhang
Aula, Vrije Universiteit Amsterdam
In vitro and cellular systems for the characterization of bioactivating and inactivating drug metabolizing enzymes in adverse drug reactions
Prof. N.P.E. Vermeulen, copromotor Dr J.N.M. Commandeur
Amsterdam Institute for Molecules, Medicines and Systems
In vitro and cellular systems for the characterization of bioactivating and inactivating drug metabolizing enzymes in adverse drug reactions: Insights into Amodiaquine idiosyncratic toxicity
Serious adverse drug reactions (ADRs) remain a significant problem during drug development and post-marketing stages. Even though extensive research has been performed, the understanding and prediction of diverse types of ADRs is still far from complete. Especially considering the most problematic ADRs, the idiosyncratic drug reactions (IDRs), which are rare and difficult to predict, whilst in several cases lethal. The formation of and human exposure to chemically reactive metabolites (CRMs) is generally considered to play an essential role in ADRs and IDRs, as it determines the internal exposure of tissues to CRMs.
During his 4 years PhD research, Yongjie Zhang has characterized the roles of several important human DMEs in the formation and elimination of CRMs of the model drug, Amodiaquine. To do so, he developed different test systems, e.g. purified enzymes and transgenic human cell lines, to investigate the formation and detoxification processes of CRMs of Amodiaquine. In addition, he measured biochemical and cellular markers representing toxifying and detoxifying profiles, and toxicity in cells to evaluate the potential toxicological outcomes as well as to understand the mode of action of human toxicity derived from Amodiaquine.
New activity assay of an important human protective DME, glutathione S-transferase (GST) T2-2
During his PhD research, Zhang also established a new method for the measurement of human GSTT2-2 enzyme activity. With this new method, which is more sensitive and reliable compared to the previously methods, a prominent role of human GSTT2-2 in the detoxification of the environmental carcinogen, 1-methylpyrene sulfate (MPS), has been proven. Moreover, it is suggested that different expression levels of human GSTT2-2 in populations might greatly influence the individual susceptibility to MPS-induced carcinogenesis.
Overall, his research identified the balance between the bioactivation and inactivation of CRMs of Amodiaquine and its potential consequences on Amodiaquine idiosyncratic toxicity. It also provided new insights into the cellular mechanisms underlying CRMs-mediated hepatotoxicity. The approaches used in this research yielded rapid, reproducible, and cost-efficient strategies for the identification of risk factors of drugs causing ADRs and IDRs and for the evaluation of potential risks of new drug candidates and chemicals.
Yongjie Zhang performed his PhD research in the AIMMS Division of Molecular Toxicology under the supervision of Prof. Nico Vermeulen and Dr Jan Commandeur. He will defend his PhD thesis on the 5th of February 2018 at 11:45 in the Aula of Vrije Universisteit Amsterdam.