Inhibition of pancreatic lipase by environmental xenoestrogens
Inhibition of pancreatic lipase by environmental xenoestrogens
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环境异雌激素对胰腺脂肪酶的抑制
DOI：
10.1016/j.ecoenv.2020.110305
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发表时间：
2020-04-01
影响因子：
6.8
通讯作者：
Ge, Guang-Bo
中科院分区：
文献类型：
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作者：
Hu, Qing;Guan, Xiao-Qing;Ge, Guang-Bo
环境雌激素是据报道对人类健康有有害影响的最容易获得的内分泌干扰化学品。尽管人们已经广泛研究了雌激素对内分泌系统的影响，但目前尚不清楚这些雌激素是否会影响哺乳动物的消化系统。本研究旨在探讨六种非甾体合成雌激素（己烯雌酚、己烯雌酚、二烯雌酚、双酚A、双酚AF和双酚Z）对哺乳动物胰脂肪酶（PL）的抑制作用及其机制。胰脂肪酶是哺乳动物脂肪消化吸收的关键消化酶。结果清楚地表明，己烯雌酚、己烯雌酚和二烯雌酚对PL具有较强的抑制作用，IC50值均小于1.0 μ m。进一步研究表明，这三种合成雌激素具有混合抑制PL的作用，其K-i值均小于1 μ m。分子动力学模拟表明，己烯雌酚及其类似物可能通过占据PL活性位点的入口，阻断底物与PL的结合，从而抑制该关键酶的水解活性。综上所述，这些结果表明己烯雌酚及其类似物是有效的PL抑制剂，可能在哺乳动物的脂质吸收和体重增加中发挥重要作用。
Environmental xenoestrogens are the most accessible endocrine disrupting chemicals that have been reported with harmful effects on human health. Although the influences of xenoestrogens on the endocrine system have been extensively studied, it remains unclear whether these xenoestrogens can affect the digestive system in mammals. This study aimed to investigate the inhibitory effects and the underlying mechanism of six nonsteroidal synthetic estrogens (including hexestrol, diethylstilbestrol, dienestrol, bisphenol A, bisphenol AF and bisphenol Z) on pancreatic lipase (PL), a key digestive enzyme responsible for lipid digestion and absorption in mammals. The results clearly demonstrated that hexestrol, diethylstilbestrol and dienestrol exhibited strong inhibition on PL, with the IC50 values of less than 1.0 mu M. Further investigations elucidated that these three synthetic estrogens functioned as mixed inhibitors of PL, with the K-i values of less than 1 mu M. Moreover, molecular dynamics simulations showed that diethylstilbestrol and its analogues might block the binding of sub-strate on PL via occupying the portal to the active site of PL and thereby inhibit the hydrolytic activity of this key enzyme. Collectively, these results suggested that diethylstilbestrol and its analogues were potent PL inhibitors, which might play a profound role in lipid absorption and weight gain in mammals.