山萘酚的作用机理研究

2011-07-27 03:50张燕玲薛小平
化学与生物工程 2011年12期
关键词:萘酚抗癌胰腺癌

张燕玲,薛小平

(西北工业大学生命学院,陕西 西安 710072)

研究表明,广泛存在于自然界中的天然多酚类物质具有优越的抗氧化、抗炎症和抗癌等生物活性[1],其中山萘酚(Kaempferol)属黄酮类黄酮醇亚属,分子式为C15H10O6,分子量为286.23,黄色晶体,熔点276~278 ℃,微溶于水,溶于二甲基亚砜、乙醇及乙醚。其结构式如下:

作者在此就近年来黄酮醇山萘酚的抗氧化、抗炎症、抗癌等细胞保护功能及作用机理进行了综述。

1 山萘酚的抗氧化作用机理

山萘酚具有抑制AGE(Advanced glycation endproducts)形成和消除自由基功能,在预防细胞内脂类及DNA氧化损伤等方面具有较强抗氧化作用[2]。现代医学研究证明,山萘酚可降低小脑粒细胞中的氧化压力[3]、抑制dRib糖诱导的成骨细胞和胰岛β-细胞的氧化损伤[4,5]。氧化压力所形成的氧化低密度脂蛋白(Oxidized low-density lipoproteins,oxLDL)可导致细胞凋亡,引起动脉粥样硬化等疾病。山萘酚具有抗脂氧化和细胞保护功能从而抑制oxLDL引发的血管平滑肌凋亡[6],此外还有助于抑制MCP-1(Monocyte chemoattractant protein-1)生成,而MCP-1在动脉粥样硬化斑(Atherosclerotic plaque)形成起始阶段具有重要作用,因此,山萘酚可抑制oxLDL的形成以及抑制巨噬细胞对oxLDL 的摄入,从而预防动脉粥样硬化[7]。

2 山萘酚的抗炎症作用机理

在对细胞因子导致的细胞粘着因子VCAM-1(Vascular cell adhension molecule-1)、ICAM-1(Intercellular adhension molecule-1)和E-selectin(Endothelial cell selectin)表达的研究中,发现这些粘着因子在动脉硬化早期起关键作用并参与炎症反应,使动脉高度硬化损伤,而以5~50 μmol·L-1山萘酚作用于血管上皮细胞即表现出明显的抗炎症作用,效果强于其结构类似物槲皮素(Quercetin)[8];研究还发现,人类口服低剂量山萘酚较槲皮素更易于吸收[9]。

山萘酚还有助于保护大脑,预防缺血性中风导致的脑损伤以及其它慢性炎症疾病。体外试验表明,山萘酚抗炎症反应与其抗氧化作用密不可分[2],山萘酚抑制一氧化氮生成,下调炎症反应中iNOS(Inducible nitric oxide synthase)、TNF-α(Tumor necrosis factor-α)、NF-κB(Nuclear factor-κB)、STAT-1(Signal transducer and activator of transcription-1)等因子的表达[10]。

3 山萘酚的抗癌作用机理

研究发现,山萘酚通过激活前凋亡因子、抗肿瘤细胞增殖和生长等作用,能够诱导肿瘤细胞凋亡并降低各种癌症如肺癌、大肠癌、卵巢癌、乳腺癌和胰腺癌等的发病率[11~15]。美国贝勒大学医学院在对胰腺癌细胞系MIA PaCa-2和Panc-1的研究中发现,以70 μmol·L-1山萘酚剂量作用4 d,癌细胞增殖分别被抑制了79%和45.7%。相比抗癌药物氟尿嘧啶(Fluorouracil),山萘酚的细胞毒性更低,并表现出明显的抑制胰腺癌细胞增殖和诱导癌细胞凋亡的作用,提示山萘酚具有降低胰腺癌发病率的功效[15]。其潜在的作用机理为提高癌细胞内部氧化压力、促使DNA降解[16]以及降低癌细胞对抗癌药物的抗性从而有助于降低癌症发病率[17]。此外,大量的研究证明,山萘酚和槲皮素协同作用较单一药物具有更为显著的抗癌疗效[18]。

4 山萘酚的其它作用及其机理

近年来研究表明,山萘酚具有降解脂肪和加快机体新陈代谢速率的作用。体外实验表明,山萘酚能诱导T3甲状腺激素(Thyroid hormone)合成和增加cAMP生成从而促进细胞能量消耗和提高细胞基础代谢率[19];体内动物实验表明,摄入山萘酚能够抑制肥胖[20]。此外,饮食中摄入适量山萘酚有助于维持健康血压水平和降低心血管疾病发病率。研究发现,Ⅱ型血管紧缩素(Angiotensin)为一种促血管收缩因子,大量存在不利于心血管健康,而山萘酚可抑制I型血管紧缩素向Ⅱ型血管紧缩素的转变,说明该化合物有利于新型心血管药物——ACE抑制剂的研发和应用[21]。

另有实验表明,山萘酚在糖尿病动物实验中表现出较好的降血糖、增加葡萄糖摄入、仿胰岛素、刺激肌糖原合成等功能[22],以及使3T3-L1脂肪细胞失去脂肪新生活性[23],其作用靶点腺苷酸激酶(AMPK)成为近年来研究的热点[24]。

5 结语

综上所述,体外和体内实验研究显示,黄酮醇山萘酚具有促进癌细胞凋亡、抵抗细胞毒性、抑制癌细胞增殖[25]、保护细胞免受氧化压力损伤[5]等功能。山萘酚的细胞保护功能可能与其调节一些关键的影响细胞活性和增殖的信号蛋白有关,如cAMP[26]、Akt激酶[27]、抗凋亡蛋白Bcl-2[28]、凋亡信号蛋白Caspase-3[29]等。

随着对山萘酚的特征及其作用机理的深入研究,逐步发现山萘酚在预防动脉粥样硬化和糖尿病、抗衰老、抗微生物感染等方面具有特殊功效[1]。随着科学的进一步发展,山萘酚的药理毒性及其对生物有机体的作用机理将被完全阐明,并最终正确有效地服务人类和社会。

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