Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1.,Chemical Research in Toxicology

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Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-09-10 , 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

Affiliation

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.

中文翻译：

Elemicin的代谢活化导致抑制硬脂酰CoA去饱和酶1。

Elemicin是存在于许多草药和香料中的天然芳香族苯基丙烷的一种成分。然而，其引起毒性的潜力仍不清楚。为了检查潜在的毒性和相关的机制，将elemicin施用给小鼠3周，并检查了血清代谢产物。在用elemicin处理的小鼠中观察到肝脏肿大，伴有血浆中不饱和和饱和的溶血磷脂酰胆碱的比例降低，并抑制了肝脏中硬脂酰CoA去饱和酶1（Scd1）mRNA的表达。给予不饱和脂肪酸油酸可降低1'-羟基lemicin（elemicin的主要氧化代谢产物）的毒性，而用SCD1抑制剂A939572治疗则可增强其毒性。此外，重组人CYP的体外使用和对人肝微粒体中CYP的化学抑制作用表明，CYP1A1和CYP1A2是负责elemicin生物激活的主要CYP。值得注意的是，CYP1A2抑制剂α-萘黄酮可以减轻小鼠对依立美霉素诱导的肝肿大的敏感性。这项研究表明，elemicin的代谢激活会导致肝脏中SCD1的抑制，这表明SCD1的上调可能是由elemicin诱导的毒性的潜在干预策略。

更新日期：2019-09-11

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