毒理學(xué)教學(xué)課件毒物的生物轉(zhuǎn)運(yùn)和生物轉(zhuǎn)化教學(xué)課件

1、BIOTRANSPOTATION AND BIOTRANSFORMATION OF TOXICANTS毒物的生物轉(zhuǎn)運(yùn)與生物轉(zhuǎn)化CHAPTER 38/3/20221 ABSORPTION CELL MEMBRANES INTRODUCTION DISTRIBUTION EXCRETION BIOTRANSFORMATION BIOTRANSPOTATION8/3/20222INTRODUCTIONDisposition process（ADME）: Absorption（吸收）Distribution（分布）Metabolism（代謝）Excretion（排泄）Page 24Biotranspr

2、otation（生物轉(zhuǎn)運(yùn)）Biotransformation（生物轉(zhuǎn)化）8/3/202238/3/20224研究外源化學(xué)物ADEM過(guò)程的意義：闡明外源化學(xué)物毒作用機(jī)制，闡明對(duì)化學(xué)物處置的種屬差異，可用于預(yù)測(cè)人類暴露化學(xué)物后的處置及在毒性中的作用。有助于闡明化學(xué)物的聯(lián)合作用機(jī)制。通過(guò)改變外源化學(xué)物的ADME過(guò)程來(lái)預(yù)防和治療化學(xué)中毒。8/3/20225攝入（ingestion）胃腸道（gastrointestinal tract）糞便（feces）吸入（inhalation）肺（lung）肝（liver）膽（bile）血液和淋巴液（blood and lymph）膀胱（bladder）尿（urin

3、e）經(jīng)皮膚（dermal）腎臟（kidney）肺臟（lung）肺泡（alveoli）呼出氣（expired air）器官（organ） 細(xì)胞外液(Extracellular fluid)腺體（gland） 分泌液 （secretions）Route of absorption, distribution and excretion of toxicant in the body.8/3/20226生物膜與生物轉(zhuǎn)運(yùn)Biological Membrane and Biotranspotation8/3/20227 Biomembrane（生物膜）APhospholipid bilayer8/3/2

4、0228Biotrospotation Mechanisms (生物轉(zhuǎn)運(yùn)的機(jī)理） Passive Transport（被動(dòng)轉(zhuǎn)運(yùn)）Simple Diffusion（簡(jiǎn)單擴(kuò)散）Filtration（濾過(guò)）Facilitated Diffusion（易化擴(kuò)散）Page 25B8/3/20229 Active Transport（主動(dòng)轉(zhuǎn)運(yùn)） Cytosis（膜動(dòng)轉(zhuǎn)運(yùn)）Endocytosis（胞吞）Exocytosis（胞吐）Phagocytosis（吞噬）Pinocytosis（胞飲）8/3/202210Passive Transport (被動(dòng)轉(zhuǎn)運(yùn)） 1. Simple Diffusion ：als

5、o be called as lipid diffusion, most toxicants cross cell membranes by simple diffusion.8/3/202211Factors Related to the Simple Diffusion The concentration gradient across the membrane. （膜兩側(cè)的濃度梯度） The lipid solubility *lipid /water partition coefficient （脂溶性：脂水分配系數(shù)） The ionization form ionization co

6、nstant, pKa （解離狀態(tài)：解離系數(shù)）8/3/2022122. 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.由于水壓和滲透壓產(chǎn)生的水流可順壓差攜帶化學(xué)物穿過(guò)膜孔。8/3/2022133. Facilitated Diffusion Facilitated diffusion i

7、s 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. 順濃度梯度，不耗能，需載體。8/3/202214Active Transport（主動(dòng)轉(zhuǎn)運(yùn)）Characters*: Chemicals are moved against concentration gradients. 逆濃

8、度梯度轉(zhuǎn)運(yùn)The transport system is saturated at high substrate concentration and exhibits a transport maximum. 轉(zhuǎn)運(yùn)量有一定極限，當(dāng)外源化學(xué)物達(dá)一定濃度時(shí)，載體可達(dá)飽和狀態(tài)。8/3/202215The transport system has the potential for competitive inhibition between compounds that are transport by the same transporter.由同一載體轉(zhuǎn)運(yùn)的兩種化學(xué)物間可出現(xiàn)競(jìng)爭(zhēng)性抑制。The

9、system requires expenditure of energy, so that metabolic inhibitors block the transport process. 該系統(tǒng)需消耗能量，因此代謝抑制劑可阻止此轉(zhuǎn)運(yùn)過(guò)程。The transport system is selective for certain structural feathers of chemical . 載體對(duì)轉(zhuǎn)運(yùn)的外源化學(xué)物有特異選擇性。8/3/202216Cytosis（膜動(dòng)轉(zhuǎn)運(yùn)） Cytosis is proposed mechanisms for cell membrane to tran

10、sport particles. Endocytosis also be called as phagocytosis when the particles are solid;the process is called pinocytosis when the particles are liquid. (吞噬 ：攝入固體； 胞飲:攝入液體；) Exocytosis is a process transport the particles out of the cells. 8/3/2022178/3/2022188/3/202219Absorption吸 收Page 268/3/20222

11、0 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.8/3/202221（1）Absorption by the Gastrointestinal Tract The GI tract is one of the most important sites

12、 where toxicants are absorbed. Absorption of toxicants can take place along the entire GI tract. Absorbed by simple diffusion, filtration, pinocytosis, even active transport. 8/3/202222 Because gastric juice is acidic and the intestinal contents are nearly neutral, the lipid solubility of weak organ

13、ic 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,

14、the reverse is true.Absorbed by passive transport in the GI tract8/3/202223影響胃腸道吸收的因素：化學(xué)物的結(jié)構(gòu)和理化性質(zhì)；胃腸蠕動(dòng)情況；胃腸道充盈程度；腸道中的細(xì)菌菌群； 8/3/202224（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 ga

15、ses, vapors of volatile or volatilizable liquids,and aerosols.8/3/202225Factors Related to the absorption in the lungs The solubility of the gas in the blood . blood/gas partition coefficient * (血/氣分配系數(shù)) The large alveolar area, high blood flow, and proximity of the blood to the alveolar air. The si

16、ze of particles.8/3/202226Schematic diagram of the absorption and translocation of chemicals by lungs.Blood（血液）Nasopharyngeal (鼻咽部）Tracheobronchial（氣管支氣管） Alveolar（肺泡）GI tract（胃腸道）Lymph(淋巴液）5m15m1m8/3/202227（3）Absorption through the Skin To be absorbed through the skin, a toxicant must pass through

17、the epidermis or appendages (sweat and sebaceous glands and hair follicles). 化學(xué)毒物經(jīng)皮吸收主要通過(guò)表皮細(xì)胞，也可通過(guò)皮膚附屬器官如毛囊、汗腺和皮脂腺等吸收（僅占0.1%1.0%）。8/3/202228Diagram of a cross section of human skin.8/3/202229The Process of Absorption through the Skin The first phase of percutaneous absorption is diffusion of the tox

18、icant through the epidermis, which, especially is its stratum corneum, is the most important barrier. 一階段：穿透階段（相）,外來(lái)化合物透過(guò)皮膚表層即角質(zhì)層的過(guò)程（是限速階段） 8/3/202230 The second phase of percutaneous absorption is diffusion of the toxicant through the dermis, which contains a porous, nonselective, aqueous diffusion

19、 medium. Toxicants pass through this area by diffusion and enter the systemic circulation.二階段：吸收階段（相）, 由角質(zhì)層進(jìn)入乳頭層和真皮層，并被吸收入血液。 吸收方式：簡(jiǎn)單擴(kuò)散8/3/202231影響皮膚吸收的因素： 外源化學(xué)物的理化性質(zhì)； 血流速度； 皮膚的完整性； 人體不同部位對(duì)吸收有差異；8/3/202232（4）Other routes of absorption Intraperitoneal(腹腔) Subcutaneous（皮下） Intramuscular（肌肉） Intravenou

20、s（靜脈）8/3/202233Distribution分 布Page 298/3/202234 After entering the blood by absorption, a toxicant is available for distribution through out the body. Distribution usually occurs rapidly. 外源化學(xué)物通過(guò)吸收進(jìn)入血液和體液后，隨血流和淋巴液分散到全身各組織的過(guò)程稱為分布。8/3/202235The distribution to the organs or tissues is determined prima

21、ry 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.器官或組織的血流量和對(duì)外源化學(xué)物的親和力是影響外源化學(xué)物分布的最關(guān)鍵的因素。在分布初始階段主要取決于器官或組織的灌流速度。8/3/202236影響化學(xué)毒物分布的因素： 血流量和速度； 組織器官與毒物的親和力； 毒物與

22、血漿蛋白質(zhì)結(jié)合； 特定組織器官的屏障：血腦屏障、胎盤屏障 貯存庫(kù)（storage depot）； 特殊的膜轉(zhuǎn)運(yùn)機(jī)制； 8/3/202237Storage depot (貯存庫(kù)） Toxicants are often concentrated in a specific tissue. The specific tissue where a toxicant is concentrated can be thought of as a storage depot.毒物蓄積部位可被認(rèn)為是貯存庫(kù)。8/3/202238Major storage depot: Plasma protein（血漿蛋白）

23、 Liver and kidney（肝和腎） Fat（脂肪組織） Bone（骨骼組織）8/3/202239Barriers Blood-brain barrier（血-腦屏障） Placental barrier（胎盤屏障） Other barriers（其他屏障）8/3/202240Excretion排 泄Page 328/3/202241 After absorption and distribution in the organism, toxicants are excreted, rapidly or slowly. They are excreted as the parent c

24、hemicals, as their metabolites,and/or as conjugates of them.化學(xué)物經(jīng)過(guò)機(jī)體吸收和分布后，就被排出體外。排泄是化學(xué)毒物及其代謝產(chǎn)物向機(jī)體外轉(zhuǎn)運(yùn)的過(guò)程，是生物轉(zhuǎn)運(yùn)的最后一個(gè)環(huán)節(jié)。 8/3/202242The 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 an

25、d milk.8/3/202243（1）Urinary ExcretionGlomerular filtration. （腎小球?yàn)V過(guò)）Tubular reabsorption.（腎小管重吸收）Tubular secretion.（腎小管分泌）8/3/202244（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

26、 the reasorption, and forming the enterohepatic circulation. 外源化合物隨膽汁進(jìn)入小腸后，有兩條去路：一部分隨同膽汁混入糞便直接排入體外；另有一部分在腸道中重新被吸收，經(jīng)門靜脈系統(tǒng)返回肝臟，再隨同膽汁排泄，形成肝腸循環(huán)（enterohepatic circulation）。 8/3/202245（3）Exhalation Substances that exist in the gaseous phase at body temperature are excreted mainly by the lungs. Volatile li

27、quids are also readily excreted via the expired air. Excretion of toxicants from the lung is accomplished by simple diffusion through the membrane.在體溫下主要以氣相存在的物質(zhì)主要通過(guò)肺排出。揮發(fā)性液體與其氣相在肺泡處于動(dòng)態(tài)平衡，也可通過(guò)肺排泄。8/3/202246（4）Other Routes of Excretion Gastrointestinal tract. Milk. Sweat and saliva.8/3/202247 The rat

28、io of the concentration of a chemical in the lipid phase to the concentration in the water phase.Lipid /water partition coefficient*脂/水分配系數(shù)指當(dāng)一種物質(zhì)在脂相和水相的分配達(dá)到平衡時(shí)，其在脂相和水相中溶解度的比值。8/3/202248blood/gas partition coefficient* The ratio of the concentration of dissolved gas in blood to the concentration in t

29、he gaseous phase.血?dú)夥峙湎禂?shù)是指在氣體或蒸汽在血中與肺泡氣中兩側(cè)分壓達(dá)到平衡時(shí)，血中的濃度與肺泡氣中濃度之比。血?dú)夥峙湎禂?shù)大的氣體或蒸汽容易進(jìn)入血液。 8/3/202249Biotransformation of Toxicants化學(xué)毒物在體內(nèi)的生物轉(zhuǎn)化8/3/202250General ConsiderationsBiotransformation is a process that, converts the parent compounds into metabolites and then forms conjugates. The most important s

30、ite of such reactions is the liver, the others being the lungs, intestine, skin, and kidney.Page 428/3/202251 In some cases, the metabolites and conjugates of the toxicants are usually more readily excretable. Biotransformation can therefore be considered a mechanism of detoxicantion by the host org

31、anism. However, in certain cases the metabolites are more toxic than the parent compounds. Such reaction may be termed “bioactivation” or “metabolic activation”. 生物轉(zhuǎn)化的意義：加速排泄；改變毒物的毒效應(yīng)性質(zhì)（如代謝解毒、代謝活化或生物活化）。8/3/202252metabolic activation products（活化代謝產(chǎn)物）： Electrophilic reagent （親電子劑） Free radical （自由基）

32、Nucleophilic reagent （親核劑，少見） Reductant-oxidant （氧化還原劑，少見）8/3/202253化學(xué)物（毒性）中間產(chǎn)物（低毒性或無(wú)毒性）產(chǎn)物（無(wú)毒性）代謝解毒代謝活化化學(xué)物（無(wú)毒性）活性中間產(chǎn)物（毒性）產(chǎn)物（無(wú)毒性）8/3/202254毒物代謝酶特征： 多態(tài)性 立體選擇性毒物代謝酶的分布： 肝 肝外組織 細(xì)胞內(nèi)分布：內(nèi)質(zhì)網(wǎng)（微粒體）；胞漿 核、線粒體、溶酶體少。8/3/202255轉(zhuǎn)化能力器官細(xì)胞強(qiáng)肝臟實(shí)質(zhì)細(xì)胞（肝細(xì)胞）肺臟Clara細(xì)胞、型上皮細(xì)胞中等腎臟近曲小管細(xì)胞小腸粘膜內(nèi)層細(xì)胞皮膚上皮細(xì)胞弱睪丸輸精管與支持細(xì)胞生物轉(zhuǎn)化的主要器官和細(xì)胞8/3/20

33、2256Biotransformation Mechanisms.Phase reactions: involving oxidation, reduction, and hydrolysis.Phase reactions: involving the production of a compound(a conjugate) that is biosynthesized from the toxicant, or its metabolits, plus an endogenous metabolite.8/3/202257Phase Biotransformation Oxidation

34、（氧化反應(yīng)） Reduction（還原反應(yīng)） Hydrolysis（水解反應(yīng)）Page 44538/3/202258Oxidation* The most important enzyme systems catalyzing the oxidative process involves microsomal cytochrome P-450 system.This system is also known as microsomal mixed function oxidase( MFO) or monooxygenase. 在氧化過(guò)程中最重要的酶系是微粒體細(xì)胞色素P-450酶系，該酶系有被

35、稱為微粒體混合功能氧化酶（MFO）或單加氧酶。8/3/202259微粒體細(xì)胞色素P-450酶系其中最重要的是依賴P-450的加單氧酶。存在部位：微粒體內(nèi)(滑面內(nèi)質(zhì)網(wǎng))催化的基本反應(yīng)RH+O2+NADPH+H+ ROH+NADP+H2O8/3/202260Consists of the P-450 system:Hemoprotein （血紅素蛋白類）Flavoprotein（黃素蛋白類）Phospholipid （磷脂類）NADPH-cytochrome P-450 reductase（NADPH-細(xì)胞色素P-450還原酶）NADH-cytochrome b5 reductase（NADH-細(xì)

36、胞色素b5還原酶）Cytochrome P-450（細(xì)胞色素P-450） Cytochrome b5（細(xì)胞色素b5）8/3/202261Oxidation - Catalyzed by P-450 system Hydroxylation of an aliphatic or aromatic carbon; (脂肪族和芳香族的羥化）8/3/202262 Epoxidation of a double bond; （雙鍵的環(huán)氧化）8/3/202263 Heteroatom oxygenation and N-hydroxylation;（雜原子氧化和N-羥化）Heteroatom dealky

37、lation;（雜原子脫烷基）Oxidative group transfer;（氧化基團(tuán)轉(zhuǎn)移）Dehydrogenation;（脫氫）Cleavgae of esters;（酯裂解）8/3/202264 micromal flavin-containing monoxygenase（微粒體含黃素單加氧酶，F(xiàn)MO）Oxidation - Catalyzed by other enzyme system Amine oxidation（氨基酸氧化） Cooxidation（共氧化反應(yīng)）8/3/202265Reduction1. Nitro reduction and Azo（偶氮）reduction2. Other types of reduction8/3/202266Hydrolysis Many toxicants contain ester-type bonds and are subject to hydrolysis. These are essentially esters, amides, and compounds of phosphate.Mammalian tissues including the plasma, liver,and kidney, contain a large number of esterase and amid