Tox path Flashcards
What enhances absorption of a substance?
Nonionized state
Lipid soluble
Where are most xenobiotics absorbed from?
Small intestine
A low volume of distribution is associated with; what is it influenced by?
Most is in the plasma, little goes into tissues; albumin levels
Where are the CYP450 enzymes in the liver?
Centrilobular hepatocytes, in SER
Where does phase I biotransformation occur? Phase II
ER; cystosol
What does phase I biotransformation require
Vitamins B2 (riboflavin), B3, B6, B9 (folic acid)
Glutathione
Flavonoids
What phase II enzyme do cats lack? What do they do instead?
Glucuronyl transferase for glucuronidation; sulfation
What does phase II biotransformation require
Also glutathione and folic acid, other B vitamins, vitamin C, magnesium, taurine,
Which CYP enzymes are in the liver? Lung?
CYP7A; CYP2F
Which CYP enzymes are in the kidney? Where are they mostly?
CYP24; straight portion of PCT
Where are most of the CYP450 enzymes in the lungs?
Club cells
Which CYP enzymes are in the adrenal cortex?
CYP21 and CYP11B
Most abundant CYP enzymes across all species?
CYP3A
WHere are most CYP450 enzymes in GI?
Villous cells of upper duodenum
What endogenous substances are toxic to the stomach? Protective?
Thromboxane A2- from platelets, causes vasoconstriction, hypoxia, and ulceration
PGE2
Pathogenesis of NSAID effect on intestines
Shift from COX to lipoxygenase pathway, so get vasoconstriction, neutrophil chemotaxis. Neutrophils cause free radical damage
What are bile acids synthesized from and where? What do they do?
Cholesterol, in the liver; emulsify fat
Where are most bile acids reabsorbed? Role of bacteria in their toxicity
Ileum; deconjugate bile salts, which can produce toxic or carcinogenic metabolites
How do trichothecene (T2 mycotoxin from Fusarium spp.), chemo, and ricin affect GI?
Cytotoxic to mitotically active crypt epithelium
How does dioxin affect GI?
Mucosal hyperplasia in stomach
How does arsenic affect GI?
Disrupts oxidative phosphorylation, endothelial damage, hemorrhage/ulceration
How do organophosphates affect GI
Are acetylcholinesterase inhibitors, so no chill- diarrhea
What hepatotoxin commonly causes apoptosis?
Fumonisin mycotoxins
What is the storage form of iron in the liver? What is it composed of? What does it form in excess?
Ferritin= ferric iron (Fe3+) and apoferritin; hemosiderin
What is copper bound to in serum? In hepatocytes?
Cerruloplasmin; Metallothionein
Pathogenesis of copper toxicity
In hepatocyte cytoplasm, acts as a ROS, causes necrosis, release of copper into circulation, causing intravascular hemolysis
What is glutathione synthesis in liver limited by?
Cysteine availability
What facilitates phase III excretion into bile? Three examples; What mediates this?
Carrier-protein mediated transporters; Mrp2, Bcrp, P-gp; Anionic tags to target the products to transporters
