tx9b00186_si_001.pdf (113.71 kB)
Effects of 26 Recombinant CYP3A4 Variants on Brexpiprazole Metabolism
journal contribution
posted on 2019-10-17, 14:42 authored by Bingbing Chen, Xiao-dan Zhang, Jian Wen, Bowen Zhang, Daoxing Chen, Shuanghu Wang, Jian-pin Cai, Guo-xin HuAs a new atypical
antipsychotic, brexpiprazole is primarily metabolized
by cytochrome P450 3A4 (CYP3A4). However, genetic polymorphisms in
CYP3A4 cause wide variability in individuals’ responses to
brexpiprazole, leading to unpredictable adverse side effects or even
therapeutic failure. The present study was designed to systematically
study the effects of 26 recombinant CYP3A4 variants on the metabolism
of brexpiprazole and investigate their enzymatic activity. Wild-type
CYP3A4 and the 26 variants were incubated with the substrate brexpiprazole
for 30 min at 37 °C. The metabolite DM-3411 was detected using
ultraperformance liquid chromatography-tandem mass spectrometry. The
activity of the wild-type CYP3A4 and 26 of its variants was analyzed.
Then, the mechanism underlying the changes in enzyme function was
observed using molecular dynamics simulations and molecular docking.
Compared with CYP3A4.1, the enzymatic activities of CYP3A4.19, -.24,
and -.28 were not significantly different (from 91.82% to 96.25%),
but CYP3A4.14 and CYP3A4.15 exhibited higher enzyme activity (from
117.9 to 127.5%). The remaining 21 isoforms, including CYP3A4.2, -.3,
-.4, -.5, -.7, -.8, -.9, -.10, -.11, -.12, -.13, -.16, -.17, -.18,
-.20, -.23, -.29, -.31, -.32, -.33 and -.34, displayed lower enzymatic
activities (from 2.90% to 75.72%). The results obtained from computer
modeling indicated that weak binding affinity impaired the function
of CYP3A4.32. Mutations that occur around the active site might lead
to a loss of enzymatic activity, while the variants located far away
from the active site perhaps had little effect on function of CYP3A4.
These comprehensive data provide a reference and prediction for treatment
strategies and risk assessments of brexpiprazole.