Target organ toxicity - Hepatotoxicity

Question 1

Why is the liver a target organ?

Answer 1

• Bloodsupply
• The function/position of the organ
• The presence of a particular enzyme or biochemical pathway
• The general vulnerability to disruption
• The ability to repair damage and regenerate
• The presence of particular uptake systems (transporters)
• Affinity to particular macromolecules
• The ability to metabolize the compound and keep the balance of its toxication/detoxication systems

Question 2

What are the major functions of the liver?

Answer 2

• Glycogen storage
• Decomposition of old blood cells
• Hormone production
• Detoxification of substances
• Production of plasma proteins
• Production of coagulation factors

Question 3

What cells are found in the liver and which contribute to the majority of the liver?

Answer 3

• Hepatocytes – 70% of the liver volume and contains the liver drug-metabolizing enzyme system
• Kupffer cells
• Sinusoidal endothelial cells
• Hepatic stellate cells

Question 4

Which enzumes are in the liver drug-metabolizing enzyme system?

Answer 4

CYP and NADPH CYP450 reductase

Question 5

Which categories are liver toxicity divided into?

Answer 5

A) Drug induced liver injury (DILI)

B) Natural toxins

C) Industrial chemicals and toxins

Question 6

What is DILI?

Answer 6

Drug induced liver injury:
- Direct or intrinsic drug reaction
Isoniazid, bromobenzene, valproic acid, CCL4
- Indirect or idiosyncratic drug reaction
Involving antibodies as e.g. Halothan anaestetic

Question 7

Which biomarkers are there for hepatotoxicity?

Answer 7

Hepatocellular necrosis (hepatitis)
- Increased Alanine aminotransaminase (ALAT) x 3-8: Warning
- Increased ALAT + Increased Bilirubin x 2-3: Danger –> Can lead to Juandice

Cholestasis
- Increased alkaline phosphatase + Increased Bilirubin –> jaundice

Steatosis (fatty liver) / chirrosis
- Macro or micro vesicular deposits / fibrosis
- Increased fat
- Indicates damage to biliary system

Question 8

What is Fatty Liver (Steatosis)?

Answer 8

Is the accumulation of triglycerides in hepatocytes.

Question 9

What is Cholestatic Damage?

Answer 9

Represent damage to the bilary system – canaliculi, ductules or the ducts.

Question 10

What is Cirrhosis?

Answer 10

Is a chronic lesion/scarring of the liver resulting from repeated injury and subsequent repair – manifested as lobules filled with fat.

It may result from either hepatocyte damage or cholestatic damage, each giving rise to a different kind of cirrhosis.

Question 11

Which drugs causes Fatty Liver (Steatosis)?

Answer 11

Alcohol hydrazine, ethionine, and tetracycline, or it may occur in combination with necrosis as with carbon tetrachloride.

Question 12

Which drugs causes Cholestatic Damage ?

Answer 12

Drugs excreted by the liver into bile are prime candidates for producing cholestatic liver disease in the susceptible patient.

Question 13

What is the toxic effect and mechanism of Nucleoside Analogues?

Answer 13

Are drugs that can cause mitochondrial damage, dysfunction of fat metabolism and liver failure.

Toxic effects: Hepatic dysfunction characterized by fatty liver and fatal liver failure.

Mechanism: They inhibit DNA polymerase and inhibit replication of mitochondrial DNA, which results in reduced numbers of mitochondria.

Question 14

What is the toxic effect and mechanism of Paracetamol?

Answer 14

Drug normally metabolized by the microsomal enzymes

Toxic effects: In overdose it can result in centrilobular hepatic necrosis.

Mechanism: The reactive intermediate NAPQI reacts with GSH –> Conjugates and or oxidizes to form GSSG
- Low GSH –> possible disturbances in intracellular calcium and glucose levels –> DNA damage
- Inhibition of Na+/K+-ATPase pump –> decrease in cellular ATP –> impaired mitochondrial function –> necrosis

Question 15

What is the antidote to paracetamol overdose?

Answer 15

Antidote: N-acetylcystein (NAC) (or methionin)
–> Promotes synthesis of glutatione (GSH

Question 16

What is the toxic effect and mechanism of Valproic acid?

Answer 16

Anti-epileptic drug

Toxic effect: can lead to DILI

Mechanism:
1. Formation of Acyl CoA acid and carnitine derivate —> CoA depletion from the mitochondrial pool
2. Further metabolization by CYP2C9 depleting mitochondrial GSH
3. Generated metabolites interfere with mitochondrial function and reduce ATP, NADH, and FADH
4. Cause inhibition of liver fat oxidation and accumulation of lipids destroying the mitochondria

Question 17

What is the toxic effect and mechanism of Bromobenzene?

Answer 17

Industrial product

Toxic effect: Centrilobular hepatic necrosis

Toxicity:
Dose dependent decrease in hepatic GSH + decrease in excretion of mercapturic acid + increase in covalent binding.

Question 18

What is the toxic effect and mechanism of Isoniazid?

Answer 18

Treatment of tuberculose

Toxic effect: Liver necrosis

Mechanism:
Metabolization by acetylation to acetyl isoniazid and further acetyl hydrazine –> Acetylisoniazid intermediates covalently bind microsomal proteins –> both metabolites give rise to liver necrosis

Question 19

What is the toxic effect and mechanism of Carbon tetrachloride?

Answer 19

CCl4, cleaning agent

Toxic effect: Chronic exposure cause liver cirrhosis and formation of liver tumours

Mechanism:
Metabolized predominantly by CYP2E1 in the liver to trichloromethyl peroxy radical –> radical can abstract a hydrogen atom from donors
OR
It may react with oxygen to form trichloromethyl peroxy radical –> centrilobular hepatic necrosis in zone 3

Question 20

What is the toxic effect and mechanism of Haloalkanes and Alkenes?

Answer 20

The toxicity involves metabolic activation however not CYP450.