药化lesson 2药物毒性的化学机制解析.ppt

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. * Background 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 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. valproic acid : liver toxicity; anaesthetics : liver injury 4. Covalent binding theory: the covalent binding of drugs to proteins is a factor contributing to drug toxicity. * Principles of reactive chemicals The 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). Free-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-radical 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 (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 after considerations of dose. Other issues (in addition to covalent binding) are receptor-mediated events (especially signal