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

Elemicin, a natural aromatic phenylpropanoid found in various herbs and spices, has unclear toxicity potential. To investigate its toxicity and underlying mechanisms, mice were treated with elemicin for three weeks, and their serum metabolites were analyzed. Elemicin treatment resulted in liver enlargement, accompanied by decreased ratios of unsaturated to saturated lysophosphatidylcholines in plasma and suppression of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in the liver. Administration of the unsaturated fatty acid oleic acid mitigated the toxicity of 1′-hydroxylelemicin, the primary oxidative metabolite of elemicin, whereas treatment with the SCD1 inhibitor A939572 exacerbated its toxicity.

Further in vitro studies using recombinant human CYP enzymes and chemical inhibition of CYPs in human liver microsomes identified CYP1A1 and CYP1A2 as the primary enzymes responsible for elemicin bioactivation. Importantly, the CYP1A2 inhibitor α-naphthoflavone reduced the susceptibility of mice to elemicin-induced hepatomegaly. These findings indicate that metabolic activation of elemicin leads to SCD1 inhibition in the liver, suggesting that upregulation of SCD1 could serve as a potential strategy to mitigate elemicin-induced toxicity.