Download largest organ - U of L Class Index

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