Perampanel (PRP), a noncompetitive
α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic
acid (AMPA) receptor antagonist with high selectivity, has been used
as a new adjuvant for the treatment of fractional seizures with or
without primary generalized tonic–clonic seizures and secondary
generalized seizures in epilepsy patients over the age of 12. Adverse
events such as liver injury have been reported during the clinical
application of PRP. The purpose of the study is to explore the in vitro and in vivo metabolic activation
of PRP. Two GSH conjugates were detected in rat liver microsomal incubations
containing PRP, GSH, and NADPH. The two GSH conjugates were both obtained
from the bile of rats and rat primary hepatocytes after exposure to
PRP. Similar microsomal incubations complemented with N-acetylcysteine (NAC) in place of GSH offered two NAC conjugates.
As expected, the NAC conjugates were detected in the urine of PRP-treated
rats. One of the two NAC conjugates was identified as NAC conjugate 12 verified by chemical synthesis. The individual human recombinant
P450 enzyme incubation assay demonstrated that CYP1A2 dominated the
catalysis for the metabolic activation of PRP. Pretreatment with α-naphthoflavone
(NTF) decreased the formation of PRP-derived GSH conjugates in both
livers of rats and cultured primary hepatocytes after being treated
with PRP. Additionally, NTF was found to decrease the susceptibility
of primary hepatocytes to the cytotoxicity of PRP. The findings indicate
that PRP was metabolized to the corresponding epoxide, which could
participate in PRP-induced cytotoxicity.
Emodin (EMD) is a major ingredient of Polygonum multiflorum Thunb. (PMT), which has shown adverse liver reactions. Despite multiple pharmacological activities, EMD is reported to show various toxicities. Our early study demonstrated the reactivity of EMD to glutathione. This study aimed to determine the covalent interaction of hepatic protein with EMD and the correlation of the protein modification with hepatotoxicity induced by EMD. EMD-derived protein adduction was detected in an incubation mixture containing mouse liver homogenates and EMD. Such protein adduction was also observed in hepatic protein obtained from mice exposed to EMD. The protein covalent binding occurred in time-and dose-dependent manners. Pretreatment of L-buthionine-sulfoximine significantly potentiated EMD-induced adduction and hepatotoxicity caused by EMD and lipopolysaccharide co-treatment. As expected, EMD-derived protein modification was observed in mouse primary hepatocytes treated with EMD. The increase in EMD exposure concentration intensified EMD-derived protein adduction and increased EMD-induced cell death. The susceptibility of hepatocytes to EMD cytotoxicity and the intensity of EMD-induced protein adduction were attenuated by the co-treatment of hepatocytes with N-acetyl cysteine. A good association of protein modification with hepatotoxicity induced by EMD was illustrated, which facilitates the understanding of the mechanism of hepatotoxicity induced by EMD.
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