HEPATOTOXICITY

Question 1

LIST THE PHASE 1 RXN THAT CONVERTS XENOBIOTICS

Answer 1

• TRANSFORMATION FROM LIPOPHILIC TO POLAR STAGE
• OXIDATION
• REDUCTION
• HYDROLYSIS

Question 2

PHASE 2 OF XYNOBIOTIC TRANSFORMATION

Answer 2

• CONJUGATION

Question 3

DISCUSS ZONE 1 OF LIVER BIOTRANSFORMATION

Answer 3

• PERIPORTAL
  
  • most aerobic
  • contains glutathione
  • glutathione perioxidase
  • alcohol dehydrogenase

Question 4

discuss zone 2 of liver cell damage

Answer 4

• gradualtransformation from zone 1 to 3
  
  • contains something of both elements

Question 5

discuss zone 3 of specific hepatic cell damage

Answer 5

• least aerobic
• contains CYP450
• CYP450 REDUCTASE
• ALSO PLACE OF LIPID SYNTHESIS

Question 6

LIST THE CHEMICALS THAT CAUSES ZONE 1 DAMAGE IN LIVER

Answer 6

1. COCCAINE
2. ALCOHOL

Question 7

LIST THE CHEMICALS THAT CAUSES AMAGE IN ZONE 2

Answer 7

SELDOMLY SPECIFIC

Question 8

LIST THE CHEMICALS THAT CAUSES AMAGE IN ZONE 3

Answer 8

• ccl4
• benzo(a) pyrine
• PCBs
• aflatoxins
• pyrrolizidine alkaloids,
• acetaminophen
  a. o.

Question 9

define cholestasis

Answer 9

Damage to canicula, causing hyperbilirubinemia

Question 10

define steatosis and where it occurs

Answer 10

• Triglyceride accumulation (zon3 damage)
• also known as fatty liver degeneration

Question 11

Dysfunctional scar tissue formation (stellate
cells)

Answer 11

cirrhosis

Question 12

toxic response of liver to cholestasis

Answer 12

• inhibition excretion of bile salts or phospholipids
• inhibition excretion via MRP2 (anions, GSH,

bilirubin)

• injury bile duct epithelium
• bile duct occlusion (bile stones)
• injury in hepatocytes

Question 13

aflatoxin produced by aspegillosus spp. that produces toxins that hurt the joints of chicken

Answer 13

Cyclopiazonic acid

Question 14

primary target organ by aflatoxin

Answer 14

liver

Question 15

secondary effect of aflatoxin

Answer 15

• reduced performance
• reduced immunity

Question 16

effects of aflotoxin on diets with low porteins

Answer 16

acute toxicity

Question 17

effects of aflotoxin on diests with high proteins

Answer 17

Increase neoplastic foci

Question 18

effects of aflatoxin on diets with low vit. A

Answer 18

increased DNA adducts

Question 19

what are the risks for AFlo in milk

Answer 19

in high producing animals
animals with subclinical mastitis are at risk
Non-conventional species: buffalos, goats, mares?

Question 20

mainbiotransformation pathways of nicine bases

Answer 20

• Hydrolysis: carboxylesterases
• N-oxidation: mainly FMO’s
• Dehydrogenation: CYP (3A, 2B/ 2C

Question 21

this liver cells are sensitive to reactive oxygen/nitrogen species

Answer 21

endothelial cells

Question 22

this cells promotes liver cirrhosis, but may also activate oval cells (liver regeneration)

Answer 22

kuffur cells

Question 23

which phase 1 activities are affected in liver function impairement

Answer 23

• (CYP450, MFO)
• mediated processing of hormones,
• neuro-transmitters (COMT) is delayed or incomplete.
• Drug metabolism (therapy) Is impaired (dose adjustment - minus 25% of the standard dose)

Question 24

which phase 11 liver activities are affected with liver function impairement

Answer 24

• conjugation activities
  
  • UDP-GT
  • GST
  • ST
  • AND OTHERS

Question 25

THE MOST TOXIC AFLOTOXIN

Answer 25

AFLATOXIN B1

Question 26

POST MORTEM APPEARANCE OF LIVER

Answer 26

* bile duct proliferation with pale livers (fatty liver syndrome) * Karyomegaly in hepatocytes Preneoplastic lesions

Question 27

WHICH ANIMALS ARE SENSITIVE TO Pyrrolizidine alkaloids

Answer 27

* horses! * Cattle and sheep with copper toxicosis

Question 28

WHICH ANIMALS ARE SENSITIVE TO Biotransformation-based toxicity:

Answer 28

horse, cattle, rat, chicken, human

Question 29

WHICH ANIMALS ARE RESISTANT TO Biotransformation-based toxicity:

Answer 29

sheep, guinea pig, hamster, gerbil

Question 30

CLINICAL SYMPTOMS OF ACUTE Pyrrolizidine alkaloids TOXICITY

Answer 30

* Liver failure (generally lethal) * - icterus/jaundice * depression (hepato-encephalopathy) * edema, ascites

Question 31

OST MORTEM CHANGES IN ACUTE LIVER TOXICITY

Answer 31

* extensive centri-lobular necrosis and hemorrhages, * karyomegaly

Question 32

CLINICAL SIGNS OF CHRONIC INTOXICATION WITH Pyrrolizidine alkaloids (PA)

Answer 32

* Rough coat, * weight loss, * weakness * Anorexia, * production losses (milk) * Photosensitation * Liver palpation: small and dense (fibrosis)

Question 33

WHICH ENZYMES ARE ELEVATED IN Pyrrolizidine alkaloids

Answer 33

* AST/ALT slighly increased, * GGT high

Question 34

WORKUP OF A PATIENT WITH Pyrrolizidine alkaloids INTOXICATION

Answer 34

* identification of exposure, * PA analyses * Histological examonation of the liver (karyomegaly, portal necrosis)

Question 35

DISCUSS PROGNOSIS OF PYRROLIZIDIN INTOXICATION

Answer 35

* Prognosis: poor (liver cirrhosis progresses even after cessation of exposure) * Caution: PAs are exerted in (dairy) milk PA’s accumulate in honey! Humans: progressive veno-occlusive liver injury with liver cirrhosis, no convincing evidence for carcinogenicity.

Question 36

DISCUSS Acetaminophen INTOXICATION IN CATS

Answer 36

* (metabolism mediated sensitivity already at low doses) * Present predominantly methemoglobinemia

Question 37

DISCUSS ACETAMINOPHEN INTOXICATION IN DOGS

Answer 37

present clear signs of liver failure (at high, repetitive doses)

Question 38

DISCUSS ACETAMINOPHEN INTOXICATION IN HUMANS

Answer 38

* liver function impairment (DILI – drug induced liver injury: auto-immune mechanism * Impairment of bile acid secretion – yellow stools

Question 39

measures to reduce liver injury

Answer 39

1. Reduce exposure 2. Reduce absorption 3. Improve elimination 4. Modulate biotransformation

Question 40

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