HEPATOTOXICITY Flashcards Preview

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Flashcards in HEPATOTOXICITY Deck (40):
1

LIST THE PHASE 1 RXN THAT CONVERTS XENOBIOTICS

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

2

PHASE 2 OF XYNOBIOTIC TRANSFORMATION

  • CONJUGATION

3

DISCUSS ZONE 1 OF LIVER BIOTRANSFORMATION

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

4

discuss zone 2 of liver cell damage

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

5

discuss zone 3 of specific hepatic cell damage

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

6

LIST THE CHEMICALS THAT CAUSES ZONE 1 DAMAGE IN LIVER

  1. COCCAINE
  2. ALCOHOL

7

LIST THE CHEMICALS THAT CAUSES AMAGE IN ZONE 2

SELDOMLY SPECIFIC

8

LIST THE CHEMICALS THAT CAUSES AMAGE IN ZONE 3

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

9

define cholestasis

Damage to canicula, causing hyperbilirubinemia

10

define steatosis and where it occurs

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

11

Dysfunctional scar tissue formation (stellate
cells)

cirrhosis

12

toxic response of liver to cholestasis 

  • 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

13

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

Cyclopiazonic acid

14

primary target organ by aflatoxin

liver

15

secondary effect of aflatoxin 

  • reduced performance
  • reduced immunity

16

effects of aflotoxin on diets with low porteins

acute toxicity

17

effects of aflotoxin on diests with high proteins

Increase neoplastic foci

18

effects of aflatoxin on diets with low vit. A

increased DNA adducts

19

what are the risks for AFlo in milk

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

20

mainbiotransformation pathways of nicine bases

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

21

this liver cells are sensitive to reactive oxygen/nitrogen species

endothelial cells

22

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

kuffur cells

23

which phase 1 activities are affected  in liver function impairement

  • (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)

24

which phase 11 liver activities are affected with liver function impairement

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

25

THE MOST TOXIC AFLOTOXIN

AFLATOXIN B1

26

POST MORTEM APPEARANCE OF LIVER

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

27

WHICH ANIMALS ARE SENSITIVE TO Pyrrolizidine alkaloids

  • horses!
    • Cattle and sheep with copper toxicosis

28

WHICH ANIMALS ARE SENSITIVE TO Biotransformation-based toxicity:

horse, cattle, rat, chicken, human

29

WHICH ANIMALS ARE RESISTANT TO Biotransformation-based toxicity:

sheep, guinea pig, hamster, gerbil

30

CLINICAL SYMPTOMS OF ACUTE Pyrrolizidine alkaloids TOXICITY

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

31

OST MORTEM CHANGES IN ACUTE LIVER TOXICITY

  • extensive centri-lobular necrosis and hemorrhages,
  • karyomegaly

32

CLINICAL SIGNS OF CHRONIC INTOXICATION WITH  Pyrrolizidine alkaloids (PA)

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

33

WHICH ENZYMES ARE ELEVATED IN Pyrrolizidine alkaloids

  • AST/ALT slighly increased,
  • GGT high

34

WORKUP OF A PATIENT WITH Pyrrolizidine alkaloids INTOXICATION

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

35

DISCUSS PROGNOSIS OF PYRROLIZIDIN INTOXICATION

  • 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.

36

DISCUSS Acetaminophen INTOXICATION IN CATS

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

37

DISCUSS ACETAMINOPHEN INTOXICATION IN DOGS

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

38

DISCUSS ACETAMINOPHEN INTOXICATION IN HUMANS

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

39

measures to reduce liver injury

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

40

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