Role of Metabolic Activation in Elemicin-Induced Cellular Toxicity

  • J Agric Food Chem. 2019 Jul 24;67(29):8243-8252. doi: 10.1021/acs.jafc.9b02137.
Yi-Kun Wang  1  2 ,  Xiao-Nan Yang  1  3 ,  Xu Zhu  1  2 ,  Xue-Rong Xiao  1 ,  Xiu-Wei Yang  4 ,  Hong-Bo Qin  1 ,  Frank J Gonzalez  5 ,  Fei Li  1
Affiliations
  • 1. State Key Laboratory of Phytochemistry and Plant Resources in West China , Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201 , China.
  • 2. University of Chinese Academy of Sciences , Beijing 100049 , China.
  • 3. Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement , Guangxi Botanical Garden of Medicinal Plant , Nanning 530023 , China.
  • 4. School of Pharmaceutical Sciences, Peking University Health Science Center , Peking University , Beijing 100191 , China.
  • 5. Laboratory of Metabolism, Center for Cancer Research , National Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , United States.
PMID: 31271289 DOI: 10.1021/acs.jafc.9b02137
Abstract

Elemicin, an alkenylbenzene constituent of natural oils of several plant species, is widely distributed in food, dietary supplements, and medicinal Plants. 1'-Hydroxylation is known to cause metabolic activation of alkenylbenzenes leading to their potential toxicity. The aim of this study was to explore the relationship between elemicin metabolism and its toxicity through comparing the metabolic maps between elemicin and 1'-hydroxyelemicin. Elemicin was transformed into a reactive metabolite of 1'-hydroxyelemicin, which was subsequently conjugated with cysteine (Cys) and N-acetylcysteine (NAC). Administration of NAC could significantly ameliorate the elemicin- and 1'-hydroxyelemicin-induced cytotoxicity of HepG2 cells, while depletion of Cys with diethyl maleate (DEM) increased cytotoxicity. Recombinant human CYP screening and CYP inhibition experiments revealed that multiple CYPs, notably CYP1A1, CYP1A2, and CYP3A4, were responsible for the metabolic activation of elemicin. This study revealed that metabolic activation plays a critical role in elemicin cytotoxicity.

Keywords
1′-hydroxyelemicin; cytotoxicity; elemicin; metabolic activation.
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