药化lesson 2-药物毒性的化学机制课件

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. 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/ductsChemical Interaction with receptorDe-toxitaionreactiveproductsDN

11、A adductsmutation, block polymerizationAdducts with Small molecules( GSH)Direct damage effectSmall amount protectiveTrigger regulatory systemsDeplete oxidative defenceLargeramountHigh amountOverwhelm: get oxidative damage to proteinsapoptosisNecrosis Proteinadducts ()effect () effectLose crucialfunc

12、tionActivate systemsto yield detrimentationresponsemetabolismSome events associated with the toxicity of drugs and xenobioticsStatin toxicity: Muscle toxicity; proteinuria and kidney failureStatins generally very good safety record in terms of their very widespread use.Their major mechanism of actio

13、n is inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in the liver, a key enzyme involved in the synthesis of cholesterol and other products of the isoprenoid pathway.Mechanism: These toxicities can be related to the direct action of the drug on the same target enzyme in the wrong

14、cell. In principle, these toxicities can be avoided with lower doses, assuming that efficacy is still maintained. Cerivastatin (西立伐他汀) was withdrawn from the market in August 2001Stretages: More potent Statin, lower the dose. Cerivastatin might therefore have been a useful drug at lower doses. In si

15、tuations of this type, one strategy is to utilize transport systems that selectively deliver the drug to the target cell for example, the organic anion transporter 1B1 (OATB) in the case of some statins.ExamplesExamplesRofecoxib (罗非昔布), a cyclooxygenase 2 (COX2) inhibitor withdrawn from the market i

16、n 2004 .Increased heart death.Mechanisms Rofecoxib, can be readily oxidized nonenzymatically to form a reactive maleimide, which indicates a possible covalent-binding explanation for the observed toxicity. Inhibition of prostacyclin synthesis leads to lack of protection from thromboxanes. There are

17、therefore several views about rofecoxib and other COX2 inhibitors that will need resolution, and interpretation will be a challenge in light of the slight increase in cardiovascular events reported in humans.10NAPQI 产生的机制11NAPQI 的氧化-还原循环NAPQI 产生的毒性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药143. 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154. 丙戊酸的毒性毒性丙戊酸的代谢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径Troglitazone185. TAZ的毒性苯并二氢吡喃环的氧化路径Troglitazone19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