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Metabolic activation of elemicin leads to the inhibition of stearoyl-CoA desaturase 1.

Xiao-nan Yang,Yi-Kun Wang,Xu Zhu,Xue-rong Xiao,Manyun Dai,Ting Zhang,Y. Qu,Xiu-wei Yang,Hong Qin,F. Gonzalez,Fei Li

Published 2019 in Chemical Research in Toxicology

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 three weeks and serum metabolites examined. Enlarged livers were observed in elemicin-treated mice, which was 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 SCD1inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

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