2. Academic Validation
  3. Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1

Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1

  • Chem Res Toxicol. 2019 Oct 21;32(10):1965-1976. doi: 10.1021/acs.chemrestox.9b00112.
Xiao-Nan Yang 1 2,  Yi-Kun Wang 1 3,  Xu Zhu 1 3,  Xue-Rong Xiao 1,  Man-Yun Dai 1 3,  Ting Zhang 1 3,  Yan Qu 1,  Xiu-Wei Yang 4,  Hong-Bo Qin 1,  Frank J Gonzalez 5,  Fei Li 1
Affiliations

Affiliations

  • 1 States Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany , Chinese Academy of Sciences , Kunming 650201 , China.
  • 2 Guangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement , Guangxi Botanical Garden of Medicinal Plant , Nanning 530023 , China.
  • 3 University of Chinese Academy of Sciences , Beijing 100049 , 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: 31468958 DOI: 10.1021/acs.chemrestox.9b00112
Abstract

Elemicin is a constituent of natural aromatic Phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 Inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

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