jf9b00893_si_001.pdf (1.42 MB)
Download fileMetabolic Activation of Myristicin and Its Role in Cellular Toxicity
journal contribution
posted on 2019-03-26, 00:00 authored by Xu Zhu, Yi-Kun Wang, Xiao-Nan Yang, Xue-Rong Xiao, Ting Zhang, Xiu-Wei Yang, Hong-Bo Qin, Fei LiMyristicin
is widely distributed in spices and medicinal plants.
The aim of this study was to explore the role of metabolic activation
of myristicin in its potential toxicity through a metabolomic approach.
The myristicin–N-acetylcysteine adduct was
identified by comparing the metabolic maps of myristicin and 1′-hydroxymyristicin.
The supplement of N-acetylcysteine could protect
against the cytotoxicity of myristicin and 1′-hydroxymyristicin
in primary mouse hepatocytes. When the depletion of intracellular N-acetylcysteine was pretreated with diethyl maleate in
hepatocytes, the cytotoxicity induced by myristicin and 1′-hydroxymyristicin
was deteriorated. It suggested that the N-acetylcysteine
adduct resulting from myristicin bioactivation was closely associated
with myristicin toxicity. Screening of human recombinant cytochrome
P450s (CYPs) and treatment with CYP inhibitors revealed that CYP1A1
was mainly involved in the formation of 1′-hydroxymyristicin.
Collectively, this study provided a global view of myristicin metabolism
and identified the N-acetylcysteine adduct resulting
from myristicin bioactivation, which could be used for understanding
the mechanism of myristicin toxicity.