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The method of safety evaluation of chemopreventive agents based on the ability of damaging human genes

基于破坏人体基因能力的化学预防剂安全性评价方法

基本信息

批准号：
10557040
负责人：
KAWANISHI Shosuke
金额：
$ 7.62万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Cancer chemoprevention is very important in preventive medicine. Attempts have been made for cancer chemoprevention using antioxidants, such as vitamins and flavonoids, which have been believed to be promising chemopreventive agents. However, a recent epidemiological study revealed that the administration of β-carotene to male smokers caused an increase in the incidence of lung cancer. In this study, to develop the method for safety evaluation of antioxidants, we examined DNA damage induced by antioxidants using human cultured cells and ^<32>P-labeled DNA fragments obtained from the human c-Ha-ras protooncogene and the p16 and p53 tumor suppressor genes. We found that β-carotene metabolites, retinol and retinal, induced DNA damage by generating reactive oxygen species in the presence of Cu(II). In human cultured cells, these metabolites caused DNA cleavage and a significant increase in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidative product of guanine, at low concentrations. Vitamin E (α-tocopherol) and N-acetylcysteine were also capable of causing oxidative DNA damage. Among the flavonoids tested, quercetin caused oxidative DNA damage in cultured cells, whereas luteolin did not. Isothiocyanates also caused oxidative DNA damage through the formation of thiol compounds. Allyl isothiocyanate caused stronger DNA damage than benzyl isothiocyanate and phenethyl isothiocyanate. These finding indicate that antioxidants can serve as proxidants, capable of causing carcinogenesis via oxidative DNA damage. The present study provided insight into the development of a sensitive method to evaluate the safety of chemopreventive agents on the basis of their DNA-damaging ability.

癌症的化学预防在预防医学中占有重要地位。已经尝试使用抗氧化剂，如维生素和类黄酮进行癌症化学预防，这些抗氧化剂被认为是有前途的化学预防剂。然而，最近的一项流行病学研究表明，对男性吸烟者服用β-胡萝卜素会导致肺癌发病率增加。在本研究中，为了开发抗氧化剂的安全性评价方法，我们使用人培养细胞和<32>从人c-Ha-ras原癌基因和p16和p53肿瘤抑制基因获得的13 P标记的DNA片段检测了抗氧化剂诱导的DNA损伤。我们发现，β-胡萝卜素代谢产物，视黄醇和视黄醇，诱导DNA损伤产生活性氧在Cu（II）的存在下。在人类培养的细胞中，这些代谢物在低浓度下引起DNA裂解和8-氧代-7，8-二氢-2 '-脱氧鸟苷（8-oxodG）（鸟嘌呤的氧化产物）形成的显著增加。维生素E（α-生育酚）和N-乙酰半胱氨酸也能引起氧化性DNA损伤。在测试的类黄酮中，槲皮素在培养的细胞中引起氧化DNA损伤，而毛地黄黄酮没有。异硫氰酸酯也通过形成硫醇化合物引起氧化DNA损伤。异硫氰酸烯丙酯对DNA的损伤作用强于异硫氰酸苄酯和异硫氰酸苯乙酯。这些发现表明，抗氧化剂可以作为致癌剂，能够通过氧化DNA损伤引起致癌。本研究提供了一个敏感的方法，以评估其DNA损伤能力的基础上的化学预防剂的安全性的发展洞察。