藥化lesson 2-藥物毒性的化學(xué)機制課件

1、藥物毒性的化學(xué)機制1.創(chuàng)新藥物化學(xué)(法)卡米爾.喬治.維爾穆特2. Elucidating Mechanisms of drug-induced toxicity. Nature, 2005, 410. 2Background 1. Almost 500 years ago, Paracelsus acknowledged that drug or poison is dose-dependent.2. Twenty-century, an exaggerated pharmacological response at the target. Such an effect would be e

2、xpected 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. valproic acid : liver toxicity; anaesthetics : liver injury4. Covalent binding the

3、ory: the covalent binding of drugs to proteins is a factor contributing to drug toxicity.3Principles of reactive chemicalsThe reaction of an electrophile and a nucleophile yields a covalent bond, which is generally irreversible (unless the product is intrinsically unstable an ester,for example). Fre

4、e-radical propagation is the basic event involved in lipid peroxidation and also in the production of radicals in DNA and proteins, events that can have a variety of detrimental effects. The basic reactions involve simple chemistry for example, reactions of electrophiles with nucleophiles and free-r

5、adical propagation. The first metabolic product or the most obvious chemical prospect might not be the reactant. The stability of reactive products 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

6、(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 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

7、 after considerations of dose. Other issues (in addition to covalent binding) are receptor-mediated events (especially signalling), ability to repair DNA and protein damage, cell proliferation and immune responses4What do we mean by toxicity?According to the pathological effect induced, Toxicity div

8、ided into 4 categories 1. Cell death/tissue injury: Tissue injury was based on the observable pathology, but establishing exactly how the death of certain cells is related to the tissue injury is often not obvious2. Altered phenotype/function: a sub-lethal response in a cell even if a cell does not

9、die, such alterations can cause major problems3. Immunological hypersensitivity : a special instance of an altered phenotype/function. It is clear that some chemicals can down-regulate immunesystem function or, alternatively, function as haptens (perhaps after metabolism and binding) or even produce

10、 autoimmunity to native proteins.4. Cancer: a type of toxic phenotype 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.6Mechanisms and contexts of drug toxicityMajor drug toxicities can be gr

11、ouped into five categories in terms of themechanism underlying toxicity: On target, or mechanism-related, toxicity; Hypersensitivity and related immunological reactions; Off target pharmacology;Biological activation to to toxic metabolites; Idiosyncratic toxicities9由尿排出毒性NAPQI乙酰氨基酚的代謝1. 乙酰氨基酚的毒性主要表現(xiàn)

12、為肝毒性。一般認(rèn)為來自代謝中間體N-乙酰-p-苯醌亞胺（NAPQI）NAPQI 是細(xì)胞成分和吡啶核苷酸的硫羥基的良好氧化劑。10NAPQI 產(chǎn)生的機制11NAPQI 的氧化-還原循環(huán)NAPQI 產(chǎn)生的毒性122. Tienilic acid （替尼酸）的毒性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藥3. 鹵代烷的毒性 麻醉藥主要（80%）由肺排出少量（15%）肝代謝肝毒性由尿排出，消毒損傷細(xì)胞大分子肝細(xì)胞死亡毒性還原途徑氧化途徑143. 鹵代烷的毒性鹵烷轉(zhuǎn)變?yōu)槿阴Ｂ群笈c蛋白的結(jié)合毒性164.丙戊酸的毒性5. TAZ的毒性口服胰島素敏化劑用于II型糖尿病 退市肝衰竭， 甚至死亡噻唑二酮環(huán)的氧化路徑Troglitazone19結(jié)論幾乎所有的代謝反應(yīng)都能產(chǎn)生活性代謝產(chǎn)物。生物體內(nèi)的這種變化可產(chǎn)生能直接或間接起作用的毒性化合物。毒性的出現(xiàn)可能是代謝物或活性中間體于生物靶相互作用的結(jié)果。烷化作用 （Alkylation)致酶失活活性氧類化合物可導(dǎo)致細(xì)胞氧化-還原形態(tài)的改變。20 發(fā)毒基團(tuán)