第八章化学致癌作用ChemicalCarcinogenesis.ppt
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1、第八章 化学致癌作用 Chemical Carcinogenesis,1、There are more than 100 types of cancers; any part of the body can be affected. 2、In 2005, 7.6 million people died of cancer - 13% of the 58 million deaths worldwide. 3、More than 70% of all cancer deaths occur in low and middle income countries. 4、Worldwide, the
2、5 most common types of cancer that kill men are (in order of frequency): lung, stomach, liver, colorectal and oesophagus.,10 facts about cancer,10 facts about cancer,5、Worldwide, the 5 most common types of cancer that kill women are (in the order of frequency): breast, lung, stomach, colorectal and
3、cervical. 6、Tobacco use is the single largest preventable cause of cancer in the world. 7、One fifth of all cancers worldwide are caused by a chronic infection, for example human papillomavirus (HPV) causes cervical cancer and hepatitis B virus (HBV) causes liver cancer.,8、A third of cancers could be
4、 cured if detected early and treated adequately. 9、All patients in need of pain relief could be helped if current knowledge about pain control and palliative care were applied. 10、40% of cancer could be prevented, mainly by not using tobacco, having a healthy diet, being physically active and preven
5、ting infections that may cause cancer.,10 facts about cancer,Based on projections, cancer deaths will continue to rise with an estimated 9 million people dying from cancer in 2015, and 11.4 million dying in 2030.,The Constitution of Causes of Death (USA,2000),1957、1984、1999、2004年我国城市主要疾病死因构成比及死因顺位,第
6、一节 化学致癌物及其分类,一、Definitions: chemical carcinogen A carcinogen is an agent whose administration to previously untreated animals leads to a statistically significant increased incidence of neoplasms of one or more histogenetic types as compared with the incidence in appropriate untreated animals. 化学致癌物
7、 能引起动物和人类肿瘤,增加其发病率或死亡率的化合物。,chemical carcinogenesis The induction or enhancement of neoplasia by chemicals. 化学致癌作用 指化学致癌物在体内引起正常细胞发生良、恶性肿瘤的过程。,Measurement of Carcinogenesis : Frequency of 1 or several types of tumors also seen in the controls Number of tumors compared to controls Development of tumo
8、rs not seen in controls Occurrence of tumors earlier in time than after exposure in the controls,二、Classifications 按作用结果分类 按作用机制分类,按作用结果分类 国际癌症研究中心(IARC) Group 1:Human Carcinogen:Sufficient evidence in humans (clear casual relationship between exposure and cancer). Examples:aflatoxin,benzene Group 2
9、: (two classifications): Group 2A: Probable Human Carcinogen :limited evidence in humans . Examples:PCBs, second-hand smoke(passive smoke) Group 2B: Possible Human Carcinogen :no evidence in humans but sufficient evidence in animals,化学致癌物分类,Group 3: Not Classifiable as a Carcinogen:limited evidence
10、in animals in the absence of human data. Examples:styrene,urethane. Group 4:Not a Human Carcinogen:negative evidence for carcinogenicity in at least 2 species. Human evidence is usually derived from occupational or accidental exposure. Example:asbestos(miners).,化学致癌物按作用结果分类(IARC分类),IARC评价的各类致癌因素的数量变
11、化,化学致癌物按作用结果分类,按作用机制分类 遗传毒性致癌物(genotoxic carcinogens )指进入细胞后与DNA共价结合,引起机体遗传物质改变,导致癌变发生的化学物质。大多数化学致癌物 直接致癌物(direct carcinogens) 间接致癌物(indirect carcinogens),化学致癌物分类,遗传毒性致癌物 直接致癌物(direct carcinogen) 这类化合物进入机体后,不需体内代谢活化而直接与细胞生物大分子(DNA,RNA,蛋白质)作用而诱导细胞癌变。 各种致癌性烷化剂和金属致癌物,化学致癌物按作用机制分类,遗传毒性致癌物 间接致癌物(indirect
12、 carcinogen) 这类化合物进入机体后需经细胞内微粒体混合功能氧化酶代谢活化后才具有致癌性。 多环芳烃类、芳香胺类、亚硝胺类、致癌性霉菌毒素和某些食物的热裂解产物等,化学致癌物按作用机制分类,前致癌物,近致癌物,终致癌物,代谢酶,代谢酶,前致癌物(precarcinogen)未经代谢活化的间接致癌物; 近致癌物(proximate carcinogen )在体内经过初步代谢转变为化学性质活泼但寿命短暂的间接致癌物; 终致癌物(ultimate carcinogen) 近致癌物进一步代谢活化,转变为带正电荷的亲电子物质,能与DNA发生反应。,非遗传毒性致癌物(nongenotoxic c
13、arcinogens)也称外遗传性致癌物(epigenetic carcinogen),指不作用于机体遗传物质的化学致癌物。主要是促进细胞过度增殖。 促癌剂、免疫抑制剂、石棉、激素,化学致癌物按作用机制分类,第二节 化学致癌物的代谢活化,化学致癌物,机体,相反应 (phase reaction),相反应 (phase reaction),氧化反应 (oxidation),还原反应 (reduction),水解反应 (hydrolysis),与谷胱甘肽结合,与葡萄糖醛酸结合,与硫酸结合,黄曲霉毒素B1(aflatoxin AFB1) 肝脏代谢 脱甲基、羟化、环氧化反应 羟化代谢产物 与谷胱甘肽、
14、葡萄糖醛酸、硫酸结合 由尿和胆汁排出 环氧化反应产物 终致癌物黄曲霉毒素B1,2,3-环氧化物 可与DNA 脱氧鸟嘌呤第7位N结合 形成加合物,化学致癌物的代谢活化,Bay region,K- region,多环芳烃(polycyclic aromatic hydrocarbons,PAH) 苯并(a)芘 benzo ( a ) pyrene,BP 代谢 羟化、环氧化反应 羟化代谢 产物与谷胱甘肽结合排出 环氧化反应 主要终致癌物7,8-二醇9,10-环氧苯并(a)芘可与DNA结合,化学致癌物的代谢活化,N-亚硝胺(nitrosamines) 二甲基亚硝胺 (dimethynitrosamin
15、e DMA) 代谢 脱甲基、脱亚硝基反应 脱亚硝基代谢 P450催化下生成醛和胺 脱甲基代谢 终致癌物甲基碳宾离子 可使核酸和蛋白质的亲核部位甲基化,化学致癌物的代谢活化,化学致癌物的代谢特点: 以氧化过程为主,形成的终致癌物具有亲电子性,能与DNA结合,造成DNA损伤,引起突变,诱发肿瘤 可在多种组织、器官中进行,具有组织器官特异性,主要以肝脏为主 人和动物对化学致癌物的代谢在种属、品系、家族和个体上的差异与遗传因素决定的代谢酶系的多态性有关,致癌物代谢酶的活性因人而异,个体间可相差30-100倍,个别的甚至可以达到1000倍,化学致癌物的代谢活化,化学致癌物与生物大分子的作用 细胞程序性死
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