BIOTRANSPOTATION AND BIOTRANSFORMATION OF TOXICANTS - PowerPoint PPT Presentation

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BIOTRANSPOTATION AND BIOTRANSFORMATION OF TOXICANTS

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  1. CHAPTER 3 BIOTRANSPOTATION AND BIOTRANSFORMATION OF TOXICANTS 毒物的生物转运与生物转化

  2. INTRODUCTION • BIOTRANSPOTATION • CELL MEMBRANES • ABSORPTION • DISTRIBUTION • EXCRETION • BIOTRANSFORMATION

  3. Biotransprotation (生物转运) Biotransformation (生物转化) Page 24 INTRODUCTION Disposition process(ADME): →Absorption(吸收) →Distribution(分布) →Metabolism(代谢) →Excretion(排泄)

  4. 研究外源化学物ADEM过程的意义: • 阐明外源化学物毒作用机制,阐明对化学物处置的种属差异,可用于预测人类暴露化学物后的处置及在毒性中的作用。 • 有助于阐明化学物的联合作用机制。 • 通过改变外源化学物的ADME过程来预防和治疗化学中毒。

  5. 摄入 (ingestion) 吸入 (inhalation) 经皮肤 (dermal) 器官 (organ) 胃肠道 (gastrointestinal tract) 肺 (lung) 血液和淋巴液 (blood and lymph) 细胞外液 (Extracellular fluid) 肝 (liver) 肾脏 (kidney) 肺脏 (lung) 胆 (bile) 膀胱 (bladder) 肺泡 (alveoli) 腺体 (gland) 粪便 (feces) 尿 (urine) 呼出气 (expired air) 分泌液 (secretions) Route of absorption, distribution and excretion of toxicant in the body.

  6. Biological Membrane and Biotranspotation 生物膜与生物转运

  7. Biomembrane(生物膜) A Phospholipid bilayer

  8. Biotrospotation Mechanisms (生物转运的机理) B • Passive Transport(被动转运) Simple Diffusion(简单扩散) Filtration(滤过) Facilitated Diffusion(易化扩散) Page 25

  9. Active Transport(主动转运) • Cytosis(膜动转运) Phagocytosis(吞噬) Pinocytosis(胞饮) Endocytosis(胞吞) Exocytosis(胞吐)

  10. Passive Transport (被动转运) 1. Simple Diffusion :also be called as lipid diffusion, most toxicants cross cell membranes by simple diffusion.

  11. Factors Related to the Simple Diffusion • The concentration gradient across the membrane. • (膜两侧的浓度梯度) • The lipid solubility — ***lipid /water partition coefficient (脂溶性:脂水分配系数) • The ionization form — ionization constant, pKa • (解离状态:解离系数)

  12. 2. Filtration When water flows in bulk across a porous membrane, any solute small enough to pass through the pores flows with it. Results from the hydrostatic and/or osmotic pressure. 由于水压和渗透压产生的水流可顺压差携带化学物穿过膜孔。

  13. 顺浓度梯度,不耗能,需载体。 3. Facilitated Diffusion Facilitated diffusion is similar to active transport but dose not move molecules against a concentration gradient. Furthermore, it is not energy-dependent, and metabolic poisons will not inhibit this process.

  14. Active Transport(主动转运) Characters**: • Chemicals are moved against concentration gradients. 逆浓度梯度转运 • The transport system is saturated at high substrate concentration and exhibits a transport maximum.转运量有一定极限,当外源化学物达一定浓度时,载体可达饱和状态。

  15. The transport system is selective for certain structural feathers of chemical . 载体对转运的外源化学物有特异选择性。 • The transport system has the potential for competitive inhibition between compounds that are transport by the same transporter. 由同一载体转运的两种化学物间可出现竞争性抑制。 • The system requires expenditure of energy, so that metabolic inhibitors block the transport process. 该系统需消耗能量,因此代谢抑制剂可阻止此转运过程。

  16. Cytosis(膜动转运) • Cytosis is proposed mechanisms for cell membrane to transport particles. • Endocytosis also be called as phagocytosis when the particles are solid;the process is called pinocytosis when the particles are liquid. (吞噬 :摄入固体; 胞饮:摄入液体;) • Exocytosis is a process transport the particles out of the cells.

  17. Page 26 Absorption 吸 收

  18. The process by which toxicants cross body membranes and enter the bloodstream is referred to as absorption. The main sites of absorption are the gastrointestinal tract, respiratory tract, and skin.

  19. (1)Absorption by the Gastrointestinal Tract The GI tract is one of the most important sites where toxicants are absorbed. Absorption of toxicants can take place along the entire GI tract. Absorbed by simple diffusion, filtration, pinocytosis, even active transport.

  20. Absorbed by passive transport in the GI tract Because gastric juice is acidic and the intestinal contents are nearly neutral, the lipid solubility of weak organic acids or bases can differ markedly in these two areas of the GI tract. e.g. Benzoic acid, which is a weak acid, exists in the stomach mainly in the nonionized form, and is thus readily absorbed. Aniline, a weak base, existing mainly in the ionized form, is poorly absorbed. In the small intestine, the reverse is true.

  21. 影响胃肠道吸收的因素: • 化学物的结构和理化性质; • 胃肠蠕动情况; • 胃肠道充盈程度; • 肠道中的细菌菌群;

  22. (2)Absorption by the Respiratory Tract The main site of absorption in the respiratory tract is the alveoli in the lungs. Toxicants absorbed by the lungs are usually gases, vapors of volatile or volatilizable liquids,and aerosols.

  23. Factors Related to the absorption in the lungs • The solubility of the gas in the blood . blood/gas partition coefficient ** (血/气分配系数) • The large alveolar area, high blood flow, and proximity of the blood to the alveolar air. • The size of particles.

  24. GI tract(胃肠道) Blood(血液) Nasopharyngeal (鼻咽部) >5μm Tracheobronchial (气管支气管) 1~5μm Alveolar (肺泡) <1μm Lymph (淋巴液) Schematic diagram of the absorption and translocation of chemicals by lungs.

  25. (3)Absorption through the Skin To be absorbed through the skin, a toxicant must pass through the epidermis or appendages (sweat and sebaceous glands and hair follicles). 化学毒物经皮吸收主要通过表皮细胞,也可通过皮肤附属器官如毛囊、汗腺和皮脂腺等吸收(仅占0.1%~1.0%)。

  26. Diagram of a cross section of human skin.

  27. The Process of Absorption through the Skin The first phase of percutaneous absorption is diffusion of the toxicant through the epidermis, which, especially is its stratum corneum, is the most important barrier. 一阶段:穿透阶段(相),外来化合物透过皮肤表层即角质层的过程 (是限速阶段)

  28. The second phase of percutaneous absorption is diffusion of the toxicant through the dermis, which contains a porous, nonselective, aqueous diffusion medium. Toxicants pass through this area by diffusion and enter the systemic circulation. 二阶段:吸收阶段(相), 由角质层进入乳头层和真皮层,并被吸收入血液。 吸收方式:简单扩散

  29. 影响皮肤吸收的因素: • 外源化学物的理化性质; • 血流速度; • 皮肤的完整性; • 人体不同部位对吸收有差异;

  30. (4)Other routes of absorption Intraperitoneal(腹腔) Subcutaneous(皮下) Intramuscular(肌肉) Intravenous(静脉)

  31. Page 29 Distribution 分 布

  32. After entering the blood by absorption, a toxicant is available for distribution through out the body. Distribution usually occurs rapidly. 外源化学物通过吸收进入血液和体液后,随血流和淋巴液分散到全身各组织的过程称为分布。

  33. The distribution to the organs or tissues is determined primary by blood flow through the organ, the rate of diffusion out of the capillary bed into the cells of a particular organ or tissue, and the affinity of components of the organ for the toxicant. 器官或组织的血流量和对外源化学物的亲和力是影响外源化学物分布的最关键的因素。 在分布初始阶段主要取决于器官或组织的灌流速度。

  34. 影响化学毒物分布的因素: • 血流量和速度; • 组织器官与毒物的亲和力; • 毒物与血浆蛋白质结合; • 特定组织器官的屏障:血脑屏障、胎盘屏障 • 贮存库(storage depot); • 特殊的膜转运机制;

  35. Storage depot(贮存库) Toxicants are often concentrated in a specific tissue. The specific tissue where a toxicant is concentrated can be thought of as a storage depot. 毒物蓄积部位可被认为是贮存库。

  36. Major storage depot: Plasma protein(血浆蛋白) Liver and kidney(肝和肾) Fat(脂肪组织) Bone(骨骼组织)

  37. Barriers • Blood-brain barrier(血-脑屏障) • Placental barrier(胎盘屏障) • Other barriers(其他屏障)

  38. Page 32 Excretion 排 泄

  39. After absorption and distribution in the organism, toxicants are excreted, rapidly or slowly. They are excreted as the parent chemicals, as their metabolites,and/or as conjugates of them. 化学物经过机体吸收和分布后,就被排出体外。排泄是化学毒物及其代谢产物向机体外转运的过程,是生物转运的最后一个环节。

  40. The principal route of excretion: • By the kidney from the urine. • By the liver and bile from the feces. • By the lung from the expired air. • Other route: sweat, saliva, tears and milk.

  41. (1)Urinary Excretion • Glomerular filtration.(肾小球滤过) • Tubular reabsorption.(肾小管重吸收) • Tubular secretion.(肾小管分泌)

  42. (2)Biliary Excretion Some toxicants are in the bile, they are excreted via the feces; however, there are exceptions, which can be hydrolyzed by intestinal flora,enabling the reasorption, and forming the enterohepatic circulation. 外源化合物随胆汁进入小肠后,有两条去路:一部分随同胆汁混入粪便直接排入体外;另有一部分在肠道中重新被吸收,经门静脉系统返回肝脏,再随同胆汁排泄,形成肝肠循环(enterohepatic circulation)。

  43. (3)Exhalation Substances that exist in the gaseous phase at body temperature are excreted mainly by the lungs. Volatile liquids are also readily excreted via the expired air. Excretion of toxicants from the lung is accomplished by simple diffusion through the membrane. 在体温下主要以气相存在的物质主要通过肺排出。挥发性液体与其气相在肺泡处于动态平衡,也可通过肺排泄。

  44. (4)Other Routes of Excretion Gastrointestinal tract. Milk. Sweat and saliva.

  45. Lipid /water partition coefficient** The ratio of the concentration of a chemical in the lipid phase to the concentration in the water phase. 脂/水分配系数 指当一种物质在脂相和水相的分配达到平衡时,其在脂相和水相中溶解度的比值。

  46. blood/gas partition coefficient** The ratio of the concentration of dissolved gas in blood to the concentration in the gaseous phase. 血气分配系数 是指在气体或蒸汽在血中与肺泡气中两侧分压达到平衡时,血中的浓度与肺泡气中浓度之比。 血气分配系数大的气体或蒸汽容易进入血液。

  47. Biotransformation of Toxicants 化学毒物在体内的生物转化