醫(yī)學(xué)]3外源化學(xué)物在體內(nèi)的生物轉(zhuǎn)運(yùn)與生物轉(zhuǎn)化-展示頁(yè)
2025-01-13 07:51本頁(yè)面
【正文】 Metabolism 1) Decrease biological activity 2) Increase excretability General Scheme of Xenobiotic Biotransformation Lipophilic Hydrophilic (parent pound) (metabolite) Phase I Phase II (oxidative) (synthetic) Metabolites Metabolites Bioactivation Detoxification Detoxification polarity functionality size ionization water solubility Increase excretability 衛(wèi)生毒理學(xué)系 生物轉(zhuǎn)化 Biotransformation ? Key ans in biotransformation – LIVER (high) – Lung, Kidney, Intestine (medium) – Others (low) ? Biotransformation Pathways * Phase Imake the toxicant more water soluble * Phase IILinks with a soluble endogenous agent (conjugation) 衛(wèi)生毒理學(xué)系 Ⅰ 相反應(yīng)發(fā)生的部位 反應(yīng)酶 部位 氧化反應(yīng) 細(xì)胞色素 P450 微粒體 黃素加單氧酶 微粒體 前列腺素 H合成酶 微粒體 醇脫氫酶 胞液 醛脫氫酶 線粒體、胞液 醛氧化酶 胞液 黃嘌呤氧化酶 胞液 單胺氧化酶 線粒體 雙胺氧化酶 胞液 反應(yīng)酶 部位 還原反應(yīng) 偶氮和硝基還原 腸道菌叢 ,微粒體 ,胞液 羰基還原 胞液、血液、微粒體 二硫還原 胞液 硫氧化物還原 胞液 醌還原 胞液、微粒體 還原脫鹵 微粒體 水解反應(yīng) 酯酶和酰胺酶 微粒體 ,胞液 ,溶酶體 ,血液 肽酶 血液、溶酶體 環(huán)氧化物水化酶 微粒體、胞液 衛(wèi)生毒理學(xué)系 Location of CYPs in the cell 衛(wèi)生毒理學(xué)系 Catalytic cycle of cytochrome P450 1. Hydroxylation of an aliphatic or aromatic carbon。 毒理學(xué)意義 衛(wèi)生毒理學(xué)系 經(jīng)肝膽排出和肝腸循環(huán) 毒物 腸道 全身其他臟器 膽汁 貯存 代謝 肝臟 消化道 血液 糞 便 解毒 排出體外 消化道不吸收 衛(wèi)生毒理學(xué)系 ? 其排泄速度與血 /氣分配系數(shù)成反比，即血?dú)夥峙湎禂?shù)越大，排泄越慢 ? 與吸收速度相反 經(jīng)肺排泄 衛(wèi)生毒理學(xué)系 其它排泄途徑 乳汁排出 脂溶性毒物如 DDT、 PCB、多溴聯(lián)苯和 TCDD等 。 衛(wèi)生毒理學(xué)系 Toxicants are eliminated from the body by several routes ? Urinary excretion ? Exhalation ? Biliary Excretion via Fecal Excretion ? CSF Milk Sweat Saliva 排 泄 Excretion 衛(wèi)生毒理學(xué)系 經(jīng)腎臟 主要排泄機(jī)理 腎小球 濾過(guò) 腎小球 簡(jiǎn)單擴(kuò)散 腎小管 主動(dòng)轉(zhuǎn)運(yùn) 膜孔 40－ 80197。如致畸物可經(jīng)過(guò)胎盤引起胚胎畸形，有些致癌物也具有經(jīng)胎盤致癌作用。 177。 177。 177。 衛(wèi)生毒理學(xué)系 The differences between diffusion and active transport 衛(wèi)生毒理學(xué)系 Passive transport ? Diffusion across a plasma membrane in which the cell expends no energy the diffusion of oxygen and carbon dioxide osmosis of water facilitated diffusion Fick定律 R＝ K A（ c1－ c2） / d R為擴(kuò)散速率， K為特定外源化學(xué)物的擴(kuò)散常數(shù)， A為生物膜的面積，（ c1－ c2）為生物膜兩側(cè)的濃度梯度， d為生物膜的厚度 脂 /水分配系數(shù) (lipid/water partition coefficient) 衛(wèi)生毒理學(xué)系 Passive Processes Water diffusion: osmotic pressure 衛(wèi)生毒理學(xué)系 Facilitated diffusion 衛(wèi)生毒理學(xué)系 Facilitated diffusion 衛(wèi)生毒理學(xué)系 Active transport 衛(wèi)生毒理學(xué)系 Three Types of Proteins for Active Transport uptake of amino acids from the intestine sodium–potassium pump calciumbinding protein 衛(wèi)生毒理學(xué)系 Primary active transport sodium–potassium (Na+–K+) pump 衛(wèi)生毒理學(xué)系 Secondary active transport 衛(wèi)生毒理學(xué)系 Xenobiotic transporters Major ABC Transporters Involved in Xenobiotic Disposition MDR1/Pgp多藥耐受蛋白或 P糖蛋白 MRP(multiresistant drug protein)多耐受藥物蛋白 ATP binding cassette (ABC) they play important roles in absorption from the GI tract and elimination into bile or into urine for a diverse array of xenobiotics. They are also critical to maintaining the barrier function of numerous tissues sites including the blood–brain barrier, the blood–testis barrier, and the maternal–fetal barrier or placenta. 衛(wèi)生毒理學(xué)系 Pgp 衛(wèi)生毒理學(xué)系 Xenobiotic transporters Major Members of the Solute Carrier Transporters Involved in Xenobiotic Disposition Solute carrier (SLC) 有機(jī)陰離子轉(zhuǎn)運(yùn)多肽 有機(jī)陰離子轉(zhuǎn)運(yùn)蛋白 有機(jī)陽(yáng)離子轉(zhuǎn)運(yùn)蛋白 肽類轉(zhuǎn)運(yùn)蛋白 肉 (毒 )堿 衛(wèi)生毒理學(xué)系 divalent metal transporter (DMT) 二價(jià)金屬離子轉(zhuǎn)運(yùn)蛋白 DMT1 previously known as NRAMP2(natural resistanceassociated macrophage protein ), was first identified in 1995 in a screening for homologues of NRAMP1, a protein involved in host defense against several types of infection. Subsequently, it was referred to as divalent cation transporter (DCT1) because of its a
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