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1、药物毒性的化学机制,1.创新药物化学(法)卡米尔.乔治.维尔穆特 2. Elucidating Mechanisms of drug-induced toxicity. Nature, 2005, 410.,醉荤瓮陷拔跑掺硬音膳枣友翠拢幅毅十磺咐债乎雍意化担迹炎掣卒丧卒娄药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,2,Background,1. Almost 500 years ago, Paracelsus acknowledged that drug or poison is dose-dependent.,2. Twenty-century, an
2、exaggerated pharmacological response at the target. Such an effect would be expected with either an overdose or impaired METABOLISM of the parent drugs.,3. Metabolic activation of drugs and other chemicals, which results from the conversion of parent compounds into products with more activity. valpr
3、oic acid : liver toxicity; anaesthetics : liver injury,4. Covalent binding theory: the covalent binding of drugs to proteins is a factor contributing to drug toxicity.,阮左忍紫治怠亿是辆盈娠缨饱了梭敌令桑堂七膘猜漏棵扯柔揖岭睁诱币楔药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,3,Principles of reactive chemicals,The reaction of an elect
4、rophile and a nucleophile yields a covalent bond, which is generally irreversible (unless the product is intrinsically unstable an ester,for example). Free-radical propagation is the basic event involved in lipid peroxidation and also in the production of radicals in DNA and proteins, events that ca
5、n have a variety of detrimental effects. The basic reactions involve simple chemistry for example, reactions of electrophiles with nucleophiles and free-radical propagation. The first metabolic product or the most obvious chemical prospect might not be the reactant. The stability of reactive product
6、s influences site and patterns of damage. A short half-life time (t1/2 = 1 s) might be considerable in a cell, and some reactive molecules are long-lived (t1/2 of min to h). In vitro systems are models, good for elucidating details. However, only some results, but not all, apply in vivo. The dose is
7、 an issue, or more properly the issue, a concept that can be traced to Paracelsus. Covalent binding can be an index of toxicity, but exceptions exist even after considerations of dose. Other issues (in addition to covalent binding) are receptor-mediated events (especially signalling), ability to rep
8、air DNA and protein damage, cell proliferation and immune responses,桔钎周帅味搭我塞师咎禾色狂踌摸裳筑帮睦捞旁咱纲叭击狱睹序痔诗启氰药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,4,What do we mean by toxicity?,According to the pathological effect induced, Toxicity divided into 4 categories 1. Cell death/tissue injury: Tissue injury was
9、based on the observable pathology, but establishing exactly how the death of certain cells is related to the tissue injury is often not obvious 2. Altered phenotype/function: a sub-lethal response in a cell even if a cell does not die, such alterations can cause major problems 3. Immunological hyper
10、sensitivity : a special instance of an altered phenotype/function. It is clear that some chemicals can down-regulate immune system function or, alternatively, function as haptens (perhaps after metabolism and binding) or even produce autoimmunity to native proteins. 4. Cancer: a type of toxic phenot
11、ype and is generally considered to involve both genotoxicity and other non-DNA aspects of cell death/tissue injury and, in some cases, altered phenotype/function.,蓉议年晾属珍牛造堰闹崔节矾谣私暂织佰透孕抡技俩贱起霍竣竖垢锹云事药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,products,Chemical,Interaction with receptor,De-toxitaion,reactiv
12、e products,DNA adducts,mutation, block polymerization,Adducts with Small molecules ( GSH),Direct damage effect,Small amount protective,Trigger regulatory systems,Deplete oxidative defence,Larger amount,High amount,Overwhelm: get oxidative damage to proteins,apoptosis,Necrosis,Protein adducts,() effe
13、ct,() effect,Lose crucial function,Activate systems to yield detrimentation response,metabolism,Some events associated with the toxicity of drugs and xenobiotics,只纹盎沧廷痴溅订痒蔑埃胡莽肯手千喳集谨蘸镶得元炔蚕摹灶晋办峪灾员药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,6,Mechanisms and contexts of drug toxicity,Major drug toxicities
14、can be grouped into five categories in terms of the mechanism underlying toxicity: On target, or mechanism-related, toxicity; Hypersensitivity and related immunological reactions; Off target pharmacology; Biological activation to to toxic metabolites; Idiosyncratic toxicities,粒逝廷西值本遇逼鲁腊沧定让狄阿径宵挣恋力唾贬息
15、勃舷落电叼易文叶愈药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,翼碰汁指兔了盼毁护我妻长穴彬搂沸抬邀冒递诺珠歼寄话愁妹来拖掺畅相药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,拂瓮世喘垣卓司瘫线羌琢绷售哈捶扑阑瞧灶贴产悦睛娜萧瓷孟隧忧校超边药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,9,由尿排出,毒性,NAPQI,乙酰氨基酚的代谢,1. 乙酰氨基酚的毒性,主要表现为肝毒性。 一般认为来自 代谢中间体 N-乙酰-p-苯醌亚胺 （NAPQI）,NAPQI 是细胞成分和 吡啶核苷酸的硫羟基 的
16、良好氧化剂。,朴云叹胡蛰工吝众搭傅惮著顷男搬淫愿酗惮掏莎灭狠径敛院皂派渠绪乡展药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,10,NAPQI 产生的机制,辖床噎慢存屈色戍兰诧巫鲍棠寒缄梭傅阐挪揪跳侗拐贤今男拴玫孩峦涌丝药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,11,NAPQI 的氧化-还原循环,NAPQI 产生的毒性,层稳测蓝早殿鲤影情兴罕翻惋搜条僚猴囱忻儡粱区诌腥到营牡掺嫩硕蚌蘑药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,12,2. Tienilic acid （替尼酸）的毒性,
17、由尿排出,自身免疫性疾病,免疫性肝炎,毒性,退市。 原因是 免疫肝炎,利尿药,兼谱兔镜静剥呛鼎昂壳袄婴隙氨食捎沃鹊扯碎者涂甫挤淋告墨剥乙闲静瓢药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,3. 卤代烷的毒性,麻醉药 主要（80%）由肺排出 少量（15%）肝代谢 肝毒性,由尿排出，消毒,损伤细胞 大分子,肝细胞死亡,毒性,还原途径,氧化途径,莆耿竖蛛勤侣钦彦臻亭尊拜期菊帘黎簇五鸦窍是饿瘦澜甩秦卵哆伦隶乔狡药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,14,3. 卤代烷的毒性,卤烷转变为三氟乙酰氯后与蛋白的结合,毒性,搞哈溪虞
18、范咀酮左弗遗穷钾扩焊延怨茬铁狼馁儿赖敦彰且延披心哭倾演修药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,15,4. 丙戊酸的毒性,毒性,丙戊酸的代谢,将凝骏撵藕皋扩溜遏式嗣酞湛奇徐窝电婴产衷埃坠童纸哥弃淄蛀壳报藐租药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,16,4.丙戊酸的毒性,你胚菲纬袁歼臼倦痉魔红袍哮赊怎捕惫危冉搭桌彬坊腮备谈忽娩孵液瞳唬药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,5. TAZ的毒性,口服胰岛素敏化剂 用于II型糖尿病,退市,肝衰竭， 甚至死亡,噻唑二酮环的氧化路
19、径,Troglitazone,波泉肆鼎点初芜裂笺冗缝之韦唁溜丑病犀氏衡侈丛胸昭昧榨蜜押次捷盟杉药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,18,5. TAZ的毒性,苯并二氢吡喃环的氧化路径,Troglitazone,纱谚医翌瘤且巳疾忱龚婴渴兑氨囤港表咱尾砂矛秦笨青动瓢冈镭衅攘秽曙药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,19,结论,几乎所有的代谢反应都能 产生活性代谢产物。生物 体内的这种变化可产生能 直接或间接起作用的毒性 化合物。 毒性的出现可能是代谢物 或活性中间体于生物靶相互作用的结果。 烷化作用 （Alky
20、lation)致酶失活 活性氧类化合物可导致 细胞氧化-还原形态的改变。,帖抿免瘤帅情岭里掷啊菠牢揽下墙禹妈缨雁诽梯铆州叮卒窥兽相脾掳渊寂药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,20,发毒基团 生物活化机制 偶氮化合物 氮烯离子，异构化正碳离子 乙烯胺 芳香/杂环胺 硝基化合物 硝基苯化合物 形成基团/氧化应力 溴芳香类 形成芳香氧化物 乙炔类 形成烯酮/破坏血红素 呋喃类 形成呋喃氧化物 吡咯类 吡咯氧化物 氮芥 吖丙啶离子 亚硝基胺 碳正离子/DNA 烷化 多卤素化合物 形成基团和亚碳化合物/与GSH形成表磺物 硫代酰胺 形成硫脲 噻吩 形成噻吩亚砜 乙烯 环氧化/破坏血红素,一些主要发毒基团及生物活化机制,烽监粤胺对磺坪拈惰绢曾鹅撞捻耿戚僵粘嘉摧萎汐久春冕篆滔赂妊虽胁篆药化lesson 2-药物毒性的化学机制药化lesson 2-药物毒性的化学机制,