外源化学物在体内的生物转运与生物转化.ppt

卫生毒理学系,第三章 外源化学物在体内的生物转运与生物转化,王取南,ANHUIMEDICALUNIVERSITY,卫生毒理学系,Toxicokinetics (毒物代谢动力学 ) how the body handles poisons Toxicodynamics (毒物效应动力学) what poisons may do to the body,Toxicokinetics refers to the processes of absorption, distribution, elimination, and metabolism of a toxicant. TK describes the changes of the concentrations of a compound in the organism over time. Toxicodynamics refers to the actions and interactions of the toxicant within the organism and describes processes at organ, tissue, cellular, and molecular levels. TD describes the dynamic interactions of a compound with a biological target and its downstream biological effects,Biotransportation (生物转运) Biotransformation (生物转化),卫生毒理学系,Toxicokinetics (Exposure 化学性质与钙类似的金属（如铅）以及能与钙形成配位体的螯合剂。,汗腺和唾液腺排出 非解离态、脂溶性毒物,头发和指甲排出 砷、汞、铅、锰等,脑脊液 主动转运参与脑脊液排出毒物的过程,卫生毒理学系,Metabolism: adverse effect depends on the concentration of active compound at the target site over time,The process by which the administered chemical (parent compounds) are modified by the organism by enzymatic reactions. 1o objective-make chemical agents more water soluble and easier to excrete decrease lipid solubility - decrease amount at target increase ionization - increase excretion rate - decrease toxicity Bioactivation-Biotransformation can result in the formation of reactive metabolites,外源化学物在体内的生物转化,卫生毒理学系,Metabolism,Decrease biological activity2) Increase excretability,General Scheme of Xenobiotic Biotransformation,Lipophilic Hydrophilic(parent compound) (metabolite),Phase I Phase II(oxidative) (synthetic),Metabolites,Metabolites,BioactivationDetoxification,Detoxification,polarityfunctionality,sizeionizationwater solubility Increase excretability,卫生毒理学系,生物转化Biotransformation,Key organs in biotransformation LIVER (high) Lung, Kidney, Intestine (medium) Others (low) Biotransformation Pathways Phase I-make the toxicant more water soluble Phase II-Links with a soluble endogenous agent (conjugation),卫生毒理学系,相反应发生的部位,卫生毒理学系,Location of CYPs in the cell,卫生毒理学系,Catalytic cycle of cytochrome P450,1. Hydroxylation of an aliphatic or aromatic carbon; 2. Epoxidation of a double bond; 3. Heteroatom (S-, N-, and I-) oxygenation and N-hydroxylation; 4. Heteroatom (O-, S-, and N-) dealkylation; 5. Oxidative group transfer; 6. Cleavage of esters; 7. Dehydrogenation.,卫生毒理学系,CYPs,Nomenclature of cytochromes P450. Members of the same family share 40% amino acid homology, and members of the same subfamily share 55% amino acid homology. there are 57 human genes and 102 mouse genes. Italics are used to designate genes, whereas mRNAs and proteins are nonitalicized by convention. http:/www.imm.ki.se/CYPalleles/ http:/drnelson.utmem.edu/CytochromeP450.html,卫生毒理学系,hydroxylation of aliphatic 二乙基酮可明显提高UDPGT代谢2-氨基酚的活性。 抑制作用（inhibition） 1. 竞争性抑制 因毒物代谢酶的底物特异性相对较低，活性有限，如同时有两种或两种以上的外源化学物为一种酶代谢，可发生竞争性抑制。 不影响酶活性及含量，是一种毒物占据酶活性中心，致其它毒物的代谢受阻。如甲醇和乙醇都由醇脱氢酶代谢。在甲醇中毒时，临床上常给予乙醇治疗。这是因为乙醇与醇脱氢酶的亲和力比甲醇强，可竞争性减缓甲醇的代谢速度而降低其毒性。,卫生毒理学系,抑制作用（inhibition）,2. 非竞争性抑制 (1) 与酶的活性中心发生可逆或不可逆性结合如-二乙基氨基苯丙基乙酯（SKF-525A）可与细胞色素P450结合而抑制其活性。苯硫磷可抑制羧酸酯酶活性使马拉硫磷的水解速度减慢而增强其毒性。 (2) 破坏酶四氯化碳、氯乙烯、肼等的代谢产物可与细胞色素P450共价结合，破坏其结构和功能。 (3) 减少酶的合成如重金属铅可抑制-氨基酮戊酸脱水酶（ALAD）和血红素合成酶活性，使血红素的合成受阻，从而抑制细胞色素P450的合成。 (4) 变构作用如CO与细胞色素P450结合后引起变构，阻碍酶与氧结合而抑制其代谢过程。 (5) 缺乏辅因子如马来酸乙二酯可耗竭GSH，使GST因缺乏辅因子而无法催化亲电子剂的结合反应。,卫生毒理学系,Thanks,