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Routes of absorption, distribution and excretion of toxicants in the body Liver major target organ of toxicants Anatomy: largest organ (1.4kg in adult man) metabolic complexity richly vascularized 1 2 Hepatic circulation Afferent blood flow: Hepatic atery (25%) Hepatic portal vein (75%) Efferent blood flow: central vein then hepatic vein then vena cava Cellular organization hepatocytes (microvili, cords) active membranes sinuses exchanges with vascular domain biliary domain adjacent hepatocytes Kupffer cells (macrophages) Ito cells (vitamin A storage) Table 13.1 3 Functional units of liver Lobule : structural unit centered around the terminal hepatic vein (THV) THV – drains lobule Acinus : Functional unit Irrigating vessels at its Base Zones 1, 2 and 3 : Metabolic regions Zone 1 close to blood Supply Zone 3 distant from Blood supply Fig.13.1 Functional units of liver Zones 1, 2 and 3 : Metabolic regions •Zone 1 close to blood supply hepatocytes irrigated with blood rich in O2 rich in untransformed toxicants higher levels of glutathione in zone 1 cells cells rich in mitochondria •Zone 2 (intermediary) •Zone 3 distant from blood supply hepatocytes irrigated with blood poor in O2 rich in biotransformation products higher levels of cytochrome P450 in zone 3 4 Hepatotoxicants Table 13.3 Biotransformation of acetaminophen – the good, the bad and the ugly Nephrotoxicity & Hepatotoxicity at excess doses 5 Gradient of bile salts in the acinus Extraction of bile salts in Zone 1 (closer to incoming blood) Levels of bile salts are low in Zone 3 Similar process occurs with hormones, drugs, xenobiotics Biotransformation of xenobiotics, Secretion into bile Uptake (extraction from blood) of solutes and toxicants by hepatocyte Biliary secretion Importance of specialized transporters MOAT (cMOAT) – canalicular multiple organic anion transporter MDR – multiple - drug resistant glycoprotein Fig.13.5 Lipophilic drugs, estrogens and lipids are exported by MDR Conjugates of glucuronides, glutathione and sulfates are exported by cMOAT Excretion of metals 6 Toxicant-induced loss of function of hepatocytes A – secretion of albumin B – uptake of bilirubin C – secretion of clotting factor H – uptake of hormones M – bioactivation Fig.13.1 Types of toxicant-induced liver injuries Table 13.2 7 Steatosis Excess accumulation of lipids in the liver (>5% w/w) Accumulation of lipid vesicles in hepatocytes Reversible, does not always cause death of hepatocyte Mechanism of action abnormal secretion of triglycerides secretion of TGs into blood blocked abnormal function of VLDL (transport lipoproteins) •e.g. CCl4, valproic acid, ethanol Cholestasis Inhibition of biliary secretion (decrease in volume of bile formed or impaired secretion into bile) Jaundice, high blood levels of bilirubin, dark urine Dilation of biliary canals Reversible May lead to cell death and inflammation if severe •e.g. Metals, drugs Normal liver 8 Steatosis cholestasis 9 Mechanisms (6) of cholestasis Fig. 13.3 Cirrhosis Accumulation of fibrous tissues, specifically collagen Formation of scar tissue (loss of function) Results from chronic, progressive liver injury (fibrosis to cirrhosis) Irreversible Fatal if severe loss of liver function •e.g. Ethanol risk of cirrhosis increases greatly in males >80g/day for 10 years in females >20g/day for 10 years (80g ET ~ 8 beers, or 8 glasses of wine or 7oz 80-proof liquor) Necrosis – cell death Cancer 10 cirrhosis Hepatoma 11 Mechanisms of microcystin hepatotoxicity specific hepatotoxicant (uptake exclusively by hepatocytes) independent of biotransformation inhibition of protein phosphatases hyperphosphorylation of cytoskeletal proteins disruption of cytoskeleton Fig.13.4 Clinical detection of liver injury Pathology Volume, weight, color, appearance (presence of lipids, collagen, tumors) Biochemical tests Plasma enzymes indicators of cholestasis: alkaline phosphatase, glutamyl transferase indicators of necrosis: lactate dehydrogenase, arginase (non specific indicators of cell death) Plasma bilirubin Liver triglycerides Covalent links, DNA adducts In vitro tests perfusion of isolated liver cell culture transporters, receptors 12