Download Toxic Response of the liver

Lecture 6
Toxic Response of the liver
The Liver
• Liver resides on the right side of the abdomen腹部 just
below the diaphragm横膈膜 .
• Receives blood from hepatic artery肝动脉 and the
portal vein门静脉 .
• Hepatic artery contain highly oxygenated blood含氧血
from systemic circulation.
• The portal vein carries less oxygenated, nutrient-rich营养
丰富 blood from the stomach and intestines.
• The first organ to encounter potentially toxic chemicals
ingested.
• Has well-developed detoxification戒毒 mechanisms.
pancreas胰腺
胆囊管
Liver functions
• Maintenance of nutrient levels in the blood including
glucose and cholesterol胆固醇
• Synthesis of proteins such as albumin清蛋白 and
factor VIII凝血因子 which are important in blood
clotting凝血and other blood functions.
• Formation and excretion of bile胆汁 via the gall bladder
胆囊
• Biotransformation and detoxification of endogenous内生
的 and exogenous外因的 agents such as bilirubin胆红
素 , ammonia, steroid hormones甾体激素 and foreign
chemicals
Liver structure
肝小叶
肝细胞
Liver structure (II)
• Anatomical structural subunit is the liver lobule:
肝小叶
– A hexagon六边形 has a portal triad at each corner
and the central vein at the center.
– Portal triad contains branches of the portal vein and
hepatic artery and a bile duct
• Blood from hepatic artery and portal vein 
portal triad  mix in penetrating vessels  flows
between hepatocytes  central vein  hepatic
vein  exit from liver.
Liver structure (III)
• Functional structural subunit of the liver is
liver acinus肝腺泡 .
• Acinus is divided into three zones:
– Zone 1: closest to the portal triad, highly
oxygenated and nutrient-rich blood.
– Zone 3: closest to the central vein, oxygenpoor, nutrient depleted blood.
– Zone 2: between zone 1 and 3
Bile formation
• Synthesis of bile
– Bile is a yellowish mixture of many compounds
including bile acids, glutathione, phospholipids,
cholesterol, bilirubin, organic anions, proteins, metals,
ions, and detoxified foreign chemicals.
– Hepatocytes肝细胞  produce bile  bile canaliculi
胆小管  bile ductules小叶内胆管  bile ducts胆
管  gall bladder  bile is secreted into a small
intestine after a meal.
– Bile acids are complexed with lipids and fat-soluble
vitamins before absorption
– Many xenobiotics are excreted from hepatocytes in
bile after their metabolism  into faeces.
胆石
Type of Hepatotoxicity肝中毒
•
•
•
•
•
•
•
Fatty liver脂肪肝
Hepatic Death
Cholestasis胆汁阻塞
Liver cirrhosis肝硬化
Inflammation炎症
Toxic effects on blood vessels and blood flow
Liver cancer
Non-alcoholic fatty liver disease非酒精性脂肪性肝病
Nonalcoholic Steatohepatitis
非酒精性脂肪性肝炎
疤痕
Fatty Liver
• Occur through excess fat synthesis, decreased
fat degradation, impaired fat secretion.
• Common and reversible acute toxic response to
many hepatotoxicants such as carbon
tetrachloride四氯化碳 and ethanol乙醇.
• An excess accumulation of lipid in the
parenchymal tissue薄壁组织
• Microscopically, the numerous lipid droplets
push aside other cellular components in the
hepatocytes.
Hepatic Death
• Hepatocyte death is the end-result of excessive
or prolonged exposure to hepatotoxic agents.
• Often preceded by fatty liver
• Due to toxic effects on the ATP-producing
mitochondria  decrease ATP
•  inactivation of many ATP-dependent functions
of the cell  alter the balance of ions and water
 accumulation of excess calcium and water in
the cells  swelling and bursting of cells  cell
dead
Hepatic Death (II)
• Most toxic agents cause Zone 3
hepatocyte death while fewer agents
induce Zone 1 or 2 death.
– Higher levels of cytochrome P450 mixed
function oxidase enzymes in Zone 3  can
produce more toxic components
– Higher levels of cytoprotective molecule,
glutathione in zone 1
Cholestasis胆汁阻塞
• Is defined as a reduction of bile formation or
impaired secretion of specific bile components.
• Occurs following injury to bile duct cells or
blockage of bile ducts.
• Several toxic agents can induce cholestasis
through the above mechanism e.g.
Methylenedianiline
•  jaundice –skin and eyes of the affected
individual appear yellowish due to the
accumulation of bilirubin
Liver Cirrhosis肝硬化
• Is the result of chronic toxic injury or
inflammation of the liver parenchyma
• Damaged tissue is replaced with fibrous
scar tissue.
• Due to repetitive exposure to hepatotoxic
chemicals e.g. ethanol
• Or chronic inflammation caused by viral
hepatitis病毒性肝炎
Liver Cirrhosis (II)
• Normally, residual hepatocytes divide and
regenerate the parenchymal tissue following a
hepatotoxic injury. If this process is impaired 
cirrhosis
• The scar tissue courses through the liver and
appears as tough, fibrous bands
• This reduces blood and bile flow  impairs the
metabolic capacity of the liver.
• Common occurrence in alcoholics
• Irreversible  liver failure and death of the
person
肝纤维化
Viral Hepatitis 病毒性肝炎 (甲、乙型病毒性肝炎 )
Inflammation发炎
• Can occur in response to chemically-induced
hepatic cell injury or as a result of viral infection.
• Characterized by the activation of Kupffer cells
枯否细胞 and the presence of other
inflammatory and immune system免疫系统
cells e.g. neutrophils中性粒细胞 , macrophages
巨噬细胞 , lymphocytes淋巴细胞 , and plasma血
浆 cells  produce toxic oxygen free radicals to
destroy foreign organisms
• But at excessive levels  also damage
parenchymal cells of the liver
Toxic effects on blood vessels and
blood flow
• Certain industrial agents can directly damage
liver endothelial cells内皮细胞 impairing损害
blood flow and secondarily affecting many
hepatic functions.
• Dacarbazine氮烯唑胺 a cancer
chemotherapeutic drug化疗药 , is more toxic to
the sinusoidal endothelial cells肝窦内皮细胞
than hepatocytes  occlusion of the sinusoid.
• Microcystin微囊藻毒素 a component of bluegreen algae, damages hepatocytes causing
them to swell and block sinusoid blood flow.
Hepatitis B virus carrier
Liver Cancer
• Many occupational chemicals (e.g. dyes, metals, solvents),
pesticides (e.g. DDT, aldrin, lindane), dietary factors and
contaminants (e.g. alcohol, aflatoxin, nitrosamines), and
pharmaceutical agents (e.g. phenobarbital, diazapam,
clofibrate) induce liver cancer.
• Most hepatic cancers develop from hepatocytes  known
as hepatocellular carcinomas原发性肝细胞癌
• Some cause the formation of liver tumors from other cells.
– Tumors from endothelial cells (hemangiosarcomas血管瘤 )
– Tumors from hepatocytes and biliary cells
(cholangiocarcinomas胆管癌 )
淋巴结
Factors that influence
Hepatotoxicity
• Biotransformation : activation pathways
• Biotransformation : Detoxification
pathways
• Potentiation增强 of Hepatotoxicity
Activation Pathways
• Generally, absorbed toxic chemicals is
metabolized in the liver to form less toxic
products  excreted in the bile and urine.
• However, some chemicals enter the liver as
nontoxic entities but are metabolized to potent
hepatotoxic products.
• Biotransformation is mediated by Cytochrome
P450 system
• Toxic products of biotransformation include
electrophilic derivatives of the parent compound
or free radicals  bind to or degrade protein or
DNA
Detoxification Pathways
• Enzyme systems, cofactors, and vitamins also exist in
the liver to detoxify the toxic metabolites and free
radicals generated by biotransformation.
• generation of toxic moieties > detoxificatyion 
hepatotoxicity
• Glutathione is a very important detoxification molecule;
glutathione transferase attached glutathione onto toxic
electrophiles  polar  easily excreted.
• Glutathione peroxidase  detoxifiy peroxides generated
by free radical reactions
• Other hepatic enzymes include Glucuronyl transferase
and sulfotransferase
• Vitamin C and E  antioxidants to protect liver cells
Potentiation of Hepatotoxicity
• Certain chemical agents can modify the
activation or detoxification of other chemicals by
–  enzyme levels,
– inactivating enzymes
–  cofactor or antioxidants
• For example, isopropanol pre-exposure or
ethanol consumption can enhance the toxicity of
carbon tetrachloride because
– Alcohols  levels of activation enzymes of carbon
tetracholoride   hepatotoxicity
Measurement of Hepatic Toxicity
• Human hepatic toxicity may be assayed by the analysis of
hepatic enzymes released into the blood from damaged liver
cells.
• serum glutamate pyruvate transaminase (SGPT谷氨酸丙酮
酸转氨酶 ) and serum glutamate oxaloacetate transaminase
(SGOT谷氨酸草酰乙酸氨基转移酶 ) are often seen following
liver toxicity, e.g. obstructive jaundice, hepatitis, metastatic
carcinoma of the liver.
• Noninvasive radiographic techniques
• Invasive techniques such as biopsy活组织检查 of the liver –
for the diagnosis of hepatocellular damage.
活组织检查