Elucidating Molecular Mechanisms of Drug-Induced Hepatotoxicity of Lapatinib
- PMID: 40712104
- DOI: 10.1021/acs.jmedchem.5c01305
Elucidating Molecular Mechanisms of Drug-Induced Hepatotoxicity of Lapatinib
Abstract
DILI (drug-induced liver injury) remains a critical liability in drug discovery and development. However, there are few in vitro and preclinical models to predict DILI, and the knowledge of DILI molecular targets is even more limited. The lapatinib (1) prescription label carries a black box warning for idiosyncratic hepatotoxicity and this has prompted numerous studies aimed at understanding the underlying molecular mechanisms. Using lapatinib as a tool molecule, we first identified a novel P450 3A5-catalyzed bioactivation, leading to highly reactive quinone methide (QM) metabolites formed after ortho- and para-hydroxylation at the 3F-benzyl ring, followed by self-immolation. The structure and activity relationship (SAR) studies of lapatinib analogs characterized the positional substitute-dependent quinone methide formation. Proteomics data revealed that quinone methide formation through bioactivation followed by simultaneous covalent modifications/functional disruption of several cellular enzymes in mitochondrial energy-production and reduction of oxidative stress could lead to mitochondrial stress and overall hepatotoxicity.
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