Metabolic activation of procarcinogens and cancer risk

致癌物的代谢激活和癌症风险

• 批准号: 06280102
• 负责人: KAMATAKI Tetsuya
• 金额: $ 102.4万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06280102/
• 关键词: P450; Salmonella typhimurium; Mutation assay; Metabolic activation; Genetic polymorphism; Lung cancer; がん原物質; トランスジェニックマウス; DNAアダクト; 発現制御; 発現系; チトクロームP450; CYP1A1; CYP1A2; アロマターゼ; Ahレセプター; 遺伝子導入マウス; がん原物質活性化; CYP3A4; P450アロマターゼ

l. Ten strains of Salmonella typhimurium YG7108 expressing each form of human cytochrome P450 (CYP), CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5, together with human NADPH-cytochrome P450 reductase (OR) have been established.2. Mutagens were formed from promutagens such as aflatoxin B_1 and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone bv human CYP forms expressed in the established Salmonella cells.3. 2-Phenylbenzotriazole derivatives, newly isolated from river water, are promutagens, were found to be activated by human CYP1A1 specifically.4. Individuals carrying a whole deletion genotype of the CYP2A6 gene showed significantly less lung cancer risk.5. Furthermore, it was found that the whole deletion of the CYP2A6 gene resulted in the low risk of small cell lung cancer and squamous cell lung cancer, which have been known to be caused associated with tobacco smoke.

L.建立了10株表达人细胞色素P450（CYP）、CYP 1A 1、CYP 1A 2、CYP 2A 6、CYP 2C 8、CYP 2C 9、CYP 2C 19、CYP 2D 6、CYP 2 E1、CYP 3A 4和CYP 3A 5以及人NADPH-细胞色素P450还原酶（OR）的鼠伤寒沙门氏菌YG 7108.利用人源大肠杆菌表达的黄曲霉毒素B_1和4-（甲基亚硝基氨基）-1-（3-吡啶基）-1-丁酮等前诱变剂形成诱变剂. 2-苯并三氮唑类化合物是一种新分离的前诱变剂，可被人CYP 1A 1特异性激活.携带CYP 2A 6基因完全缺失基因型的个体显示出显著更低的肺癌风险。此外，发现CYP 2A 6基因的整个缺失导致小细胞肺癌和鳞状细胞肺癌的低风险，已知这些癌症与烟草烟雾有关。

项目成果

N.Ariyoshi, T.Kamataki et al.: "A high level expression of CYP2A in the lung of the Suncus (Suncus murinus) and its role in the Activation of 4-(methylntirosamino)-1-(3-pyridyl)-1-butanone (NNK)"Biochem.Biophys.Res.Commun.. (In press). (2000)

N.Ariyoshi、T.Kamataki 等人：“CYP2A 在 Suncus (Suncus murinus) 肺中的高水平表达及其在 4-(methylntirosamino)-1-(3-pyridyl)-1 激活中的作用

Y.Sugiyama et al.: "Prediction of in vivo nonlinear first-pass hepatic metabolism of YM796 from in vivo metabolic data." J.Pharmacol.Exp.Ther.286. 122-127 (1998)

Y.Sugiyama 等人：“根据体内代谢数据预测 YM796 的体内非线性首过肝代谢。”

加藤隆一・鎌滝哲也編: "薬物代謝学-医療薬学・毒性学の基礎として-" 東京化学同人, 225 (1995)

Ryuichi Kato 和 Tetsuya Kamataki（编）：“药物代谢 - 作为医学药理学和毒理学的基础”东京化学同人，225（1995）

Kamataki,T.: "Fetus-specific CYP3A7 and adult-specific CYP3A4 expressed in Chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins." Cancer Res.55. 787-791 (1995)

Kamataki,T.：“中国仓鼠 CHL 细胞中表达的胎儿特异性 CYP3A7 和成人特异性 CYP3A4 具有相似的激活致癌霉菌毒素的能力。”

Y.Takahashi, K.Nakayama, T.Kamataki, et al.: "Cooperative regulation of CYP2C12 gene expression by signal transducer and activator of transcription 5 (STAT5) and liver-specific factor in female rats"J. Biol. Chem.. 274. 37117-37124 (1999)

Y.Takahashi、K.Nakayama、T.Kamataki 等人：“雌性大鼠中信号转导器和转录激活剂 5 (STAT5) 以及肝脏特异性因子对 CYP2C12 基因表达的协同调节”J.