Many
herbal medicines such as epimedium have been
reported to cause adverse effects, and icaritin is the common aglycone
of many glucosides in epimedium. Our present work
aimed at the clarification of the metabolic activation of icaritin
possibly responsible for the adverse effects of epimedium. A quinone methide metabolite (M1) was detected in icaritin-fortified
microsomal incubations. A glutathione (GSH) conjugate (M2) and N-acetyl-l-cysteine (NAC) conjugate (M3) derived
from icaritin were observed in GSH/NAC-supplemented rat/human liver
microsomal incubations. CYP3A family was the predominant enzyme catalyzing
the bioactivation of icaritin. In conclusion, sufficient evidence
indicates the metabolic activation of icaritin to quinone methide
metabolite.
α-Asarone
(αA) and β-asarone (βA) are often
used as flavoring agents for alcoholic beverages and food supplements.
They possess a double bond in the side chain with different configurations.
Double bonds are a class of alert chemical group, due to their metabolic
epoxidation to the corresponding epoxides eliciting liver injury.
Little is known about changes of configuration on metabolic activation
and related toxicity. Here, we report the insight into the mechanisms
of hepatotoxicity of asarone with different configurations. In vitro
and in vivo comparative studies demonstrated βA displayed higher
metabolic activation effectiveness. Apparently, the major metabolic
pathway of βA underwent epoxidation at C-1′ and C-2′,
while αA was mainly metabolized to the corresponding alcohol
resulting from the hydroxylation of C-3′. CYP1A2 dominated
the metabolism of αA and βA. The molecular simulation
studies showed that the orientation of βA at the active site
of CYP1A2 favored the epoxidation of βA over that of αA.
These findings not only remind us that configuration is another important
factor for toxicities but also facilitate the understanding of the
mechanisms of toxic action of asarone. Additionally, these findings
would benefit the risk assessment of αA and βA exposure
from foods.
Plocabulin (PM060184) is a promising new anticancer drug as a microtubule inhibitor. The conformational structure and properties of plocabulin have been studied theoretically. The initial structure was screened by the B3LYP/3-21G* method, and then 32 unique conformations were further optimised with the B3LYP/6-311G* method. The single-point energies were determined at the M06-L/6-311G(2df,p) level. The UV excitation of the most stable plocabulin conformation in methanol was studied by the TD-CAM-B3LYP/6-311G(2df,p) method. High-quality human p-glycoprotein model was obtained through homology modelling. The binding interaction between p-glycoprotein and plocabulin was studied by docking and MD simulation. LEU65, TYR310, ILE340, THR945, PHE983, MET986, and GLN990 were found to be important amino acid residues in the interaction. From a certain perspective, the ‘reverse exclusion’ mechanism of plocabulin with p-glycoprotein was illustrated, and this mechanism provides theoretical guidance for the structural modification of plocabulin and for design of drug’s to avoid p-glycoprotein-mediated drug resistance.
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