Ebook A textbook of modern toxicology (4/E): Part 2
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Ebook A textbook of modern toxicology (4/E): Part 2
PART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2al toxins and many man-made chemicals including industrial compounds, pesticides, and pharmaceutical drugs. Mechanisms of hepatotoxicity arc well understood for several chemicals such as halogenated solvent CCI4 and analgesic acetaminophen. Drug induced liver injury (DILI) remains one the major reas Ebook A textbook of modern toxicology (4/E): Part 2ons for new drugs to fail to meet regulatory approval. The progressive injury to the liver due to repeated exposure to toxic doses of ethanol remainsEbook A textbook of modern toxicology (4/E): Part 2
a leading human health concern. The liver has many critical functions in the body, and the unique structures and functions of the liver are important PART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2ture of the hepatic parenchyma consists of rows of functionally diverse hepatocytes separated by spaces called sinusoids (sec Chapter 9. Figure 9.2). Blood Mows into the sinusoidal spaces via the hepatic portal vein blood from the gastrointestinal ((H) tract, which is the main blood supply, and oxyg Ebook A textbook of modern toxicology (4/E): Part 2enated blood also enters from the hepatic artery. Blood subdivides and drains into the sinusoids then exits via the terminal hepatic venule (TIIV) orEbook A textbook of modern toxicology (4/E): Part 2
central vein.The blood that perfuses the liver exits by these hepatic veins, which merge into the inferior vena cava and return blood to the heart. ThPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2es differ in size and functions.Although hepatocytes comprise the majority of liver cells, other non parenchymal cells arc present in sizable numbers al specific locations (Figure I3.I). Bile duel epithelial cells are located in portal triads and endothelial cells line the sinusoids. Kupffer cells a Ebook A textbook of modern toxicology (4/E): Part 2re macrophages, which engulf and destroy materials such as solid particles, bacteria, and dead blood cells, and are attached to the intralumenal sideEbook A textbook of modern toxicology (4/E): Part 2
of the sinusoidal wall, while hepatic stellate cells (IISCs) (also known as fat-storingA Textbook of Modern Toxicology, Fourth Edition. Edited by Fi nPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2tial relationship. HC, hepatocytes: Ku. Kupffer cells: En. vascular endothelial cells: St. Stellate (Ito) cells: NK. lymphocytes.or Ito cells) are in the perisinusoidal space of Disse. a region between the sinusoidal endothelium and hepatocytes. In chemically injured liver, the periportal region can Ebook A textbook of modern toxicology (4/E): Part 2 become populated with a morphologically distinct cell, the "oval" cell, which is thought to be a stem cell capable of differentiating into either hepEbook A textbook of modern toxicology (4/E): Part 2
atocytes or bile duct epithelia.Other materials, such as bile acids and many xenobiotics. move from the hepatocytes into the bile from their sites of PART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2 duct from which bile drains into the upper part of the small intestine, the duodenum. The gall bladder, in all species but rat. serves to hold bile until it is emptied into the intestine.13.1.2Liver FunctionThe liver has many important physiological functions that impact the body, but the liver's t Ebook A textbook of modern toxicology (4/E): Part 2hree main functions include storage, metabolism, and biosynthesis, and the heterogeneity of hepatocytes in the conduct of these functions occurs largeEbook A textbook of modern toxicology (4/E): Part 2
ly differentiated by position along the sinusoid. Glucose is converted to glycogen and stored as needed for energy, and is converted back to glucose aPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2 in the liver. Fatty acids are metabolized and converted to lipids, which are then conjugated with proteinsTYPES OF LIVER INJURY 279synthesized in the liver and released into the bloodstream as lipoproteins. The liver also synthesizes numerous functional proteins, such as enzymes and plasma proteins Ebook A textbook of modern toxicology (4/E): Part 2 including blood-coagulating factors. In addition, the liver, which contains numerous xenobiotic metabolizing enzymes, is the main site of xenobioticEbook A textbook of modern toxicology (4/E): Part 2
metabolism, which predominates in the centrilobular hepatocytes. Liver metabolism of xenobiotics absorbed from the gut can greatly reduce the xenobiotPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2 body, is often the target organ for chemically induced injuries. Several important factors are known to contribute to the liver’s susceptibility. First, most xenobiotics enter the body through the GI tract and. after absorption, are transported by the hepatic portal vein to the liver. Thus, the liv Ebook A textbook of modern toxicology (4/E): Part 2er is the first organ perfused by chemicals that are absorbed in the gut and is exposed to the highest concentrations of xenobiotics. A second factorEbook A textbook of modern toxicology (4/E): Part 2
is the high concentration in the liver of xenobiotic metabolizing enzymes, primarily the cytochrome P-450-dependent monooxygenase system. Although mosPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2 induce lesions within the liver. Often, areas of damage are in the centrilobular region, as hepatocytes in this localization have the highest concentration of cytochrome P450s (CYPs). and therefore, the greatest amount of reactive metabolites are produced in this region. Third, the process of bile Ebook A textbook of modern toxicology (4/E): Part 2formation and movement of bile to the GI tract can concentrate xenobiotics that are transported with the bile. Xenobiotics and most of the bile releasEbook A textbook of modern toxicology (4/E): Part 2
ed into the intestines are reabsorbed and transported back to the liver by the hepatic portal circulation, which can increase the concentration of xenPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2ological morphology. Intrinsic hepatotoxicants demonstrate broad incidence, dose-dependent relationship, and usually similar toxicities are seen in humans and animal models. Idiosyncratic hepatotoxicants demonstrate limited toxicity seen in susceptible individuals and results from hypersensitivity o Ebook A textbook of modern toxicology (4/E): Part 2r unusual metabolic conversions that may occur due to polymorphisms in drug metabolizing genes.The types of injury to the liver depend on the type ofEbook A textbook of modern toxicology (4/E): Part 2
toxic agent, the severity of intoxication, and whether the type of exposure is acute or chronic. The main types of liver damage are discussed briefly PART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2tty liver), cholestasis, fibrosis, and necrosis, or apoptosis. Whereas some types of damage—for example, cholestasis—are liver specific, others such as necrosis and carcinogenesis are a more general phenomena. Damaged liver cells release liver-specific enzymes such as alanine aminotransferase (ALT). Ebook A textbook of modern toxicology (4/E): Part 2aspartate aminotransferase (AST).and alkaline phosphatase into the blood.280 HEPATOTOXICITYThe enzymes ALT and AST arc used as biomarkers of injured hEbook A textbook of modern toxicology (4/E): Part 2
epatocytes, while alkaline phosphatase indicates bile duel epithelial damage. Ihcsc enzymes arc commonly monitored clinically and in animal studies toPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2des, due to an imbalance between the uptake of extrahepatic triglyccreidcs and the hepatic secretion of triglyccridc-conlaining lipoproteins and fatly acid catabolism. Although many toxicants may cause lipid accumulation in the liver ( Table 13.1), the mechanisms may be different. Basically, lipid a Ebook A textbook of modern toxicology (4/E): Part 2ccumulation is related to disturbances in cither the synthesis or the secretion of lipoproteins. Excess lipid can result from an oversupply of free faEbook A textbook of modern toxicology (4/E): Part 2
tty acids from adipose tissues or. more commonly, from impaired release of triglycerides from the liver into the plasma. Triglycerides are secreted frPART VORGAN TOXICITYCHAPTER 13HepatotoxicityANDREW D. WALLACE and SHARON A. MEYER13.1INTRODUCTIONHepatotoxicity is a consequence of exposure to natura Ebook A textbook of modern toxicology (4/E): Part 2epatotoxic Agents and Associated Liver InjuryNecrosis and Fatty LiverCarbon tetrachlorideDimethylnitrosaminePhosphorousChloroform Trichloroethylene Tetrachloroethylene Bromobenzene Thioacetamide Ethionine TroglitazoneCyclohexamide Tetracycline Acetaminophen Mitomycin Puromycin Tannic acid Zidovudine Ebook A textbook of modern toxicology (4/E): Part 2 (AZT)Beryllium Allyl alcohol Galactosamine Azaserine Aflatoxin pyrrolizidine alkaloidsCholestasis (Drug Induced)Chlorpromazine Promazine ThioridazineEbook A textbook of modern toxicology (4/E): Part 2
Mepazine Amitriptyline PhenytoinImipramine Diazepam Methandrolone Mestranol EstradiolCarbarsone Chlorthiazide Methimazole Sulfanilamide PhenindioneGọi ngay
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