Elucidating Molecular Mechanisms of Drug-Induced Hepatotoxicity of Lapatinib

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.