tailieunhanh - Ebook A textbook of modern toxicology (4/E): Part 2

(BQ) Part 2 book “A textbook of modern toxicology” has contents: Hepatotoxicity, toxicology of the nervous system, reproductive system, endocrine toxicology, respiratory toxicology, immune system, toxicity testing, forensic and clinical toxicology, and other contents. | PART V ORGAN TOXICITY CHAPTER 13 Hepatotoxicity ANDREW D. WALLACE and SHARON A. MEYER INTRODUCTION Hepatotoxicity is a consequence of exposure to natural toxins and many man-made chemicals including industrial compounds, pesticides, and pharmaceutical drugs. Mechanisms of hepatotoxicity are well understood for several chemicals such as halogenated solvent CCl4 and analgesic acetaminophen. Drug induced liver injury (DILI) remains one the major reasons for new drugs to fail to meet regulatory approval. The progressive injury to the liver due to repeated exposure to toxic doses of ethanol remains 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 reasons for the liver’s susceptibility to chemical toxicity. Liver Structure The liver consists of a variety of cell types, but the basic architecture of the hepatic parenchyma consists of rows of functionally diverse hepatocytes separated by spaces called sinusoids (see Chapter 9, Figure ). Blood flows into the sinusoidal spaces via the hepatic portal vein blood from the gastrointestinal (GI) tract, which is the main blood supply, and oxygenated blood also enters from the hepatic artery. Blood subdivides and drains into the sinusoids then exits via the terminal hepatic venule (THV) or 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. The hepatocytes located near the THV are referred to as centrilobular, while those near the portal vein are periportal hepatocytes, and these hepatocytes differ in size and functions. Although hepatocytes comprise the majority of liver cells, other nonparenchymal cells are present in sizable numbers at specific locations (Figure ). Bile duct epithelial cells are located in portal triads and endothelial cells line the sinusoids. Kupffer cells are macrophages, which engulf and