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38 Cards in this Set

  • Front
  • Back
What is a xenobiotic?
A chemical or substance that is foreign to an organism or biological system.
Xenobiotics may be what?
1. Natural

2. Synthetic (additives, pesticides, contaminants, etc)
For a chemical to enter a cell and exert its action what must it be?
Lipophilic (if it is hydrophilic it will enhance its removal from the body)
What influences the action of a drug?
Biotranformation (drug metabolism)
Biotransformation activates a drug by converting a ? to a ?.
Activates a prodrug to a drug.
Biotransformation may cause either a ? or ? change in action.
Quantitative or qualitative change.
Biotransformation may ? or ? the toxicity of a substance.
May enhance or antagonize the toxicity of a substance.
What might be a biomarker of exposure to a substance?
Detection of its metabolites.
Where do biotranformations occur?
"everywhere"...BUT the highest levels are observed at:

Portals of entry and exit (alimentary tracts, LIVER, lungs, kidneys, upper respiratory tract, skin)

(prominent in epithelial cells)
Why is the liver considered an important site of biotransformation?
It is important because of the first pass effect. This is the 1st major organ to see drugs systemically. Once a chemical hits the liver it is considered systemic. The majority of cells here are capable of drug enzyme interactions.
What is the "double-edged sword" involved in the localization of biotransformationn enzymes?
1. First pass detoxification at sites of drug entry. (Presystemic metabolism)

2. Sites of drug entry become targets for toxic and carcinogenic metabolites

(Cancer - Olfactory, intestinal, hepatic)

(Target toxicity - liver, kidney, lungs...not necessarily the site of entry but increased target toxicity because they metabolize xenobiotics.
What are the three 'levels' of distribution in the localization of biotransformation enzymes?
Organ distribution-->Regional distribution-->Cellular distribution
What are the two areas of possible regional distribution in the liver?
Centrilobular vs. Periportal
What are the tow areas of possible regional distribution in the kidney?
Renal cortex vs. Medulla
Why is the study of the localization of biotransformation enzymes important?
Used in safety evaluations. (specialized tests)

1. In vitro systems to predict human metabolites

2. In vitro systems (S-9) to detect mutagens and predict carcinogens (Ames test)

3. In vitro systems to predict human carcinogens

4. Identify metabolites for in vivo analysis

5. Unique approaches for antidotal therapy
What is enterohepatic recycling?
When a xenobiotic keeps going back to the GI tract and getting reabsorbed; stays in body.

This is an advantage in the field of toxicology. It aids in the removal of certain poisons like Digitoxin/Kepone that can be trapped in the intesting with nonabsorbable resin like Questran (cholestyramine).
Biotranformation via pathways of intermediary metabolism may result in what?

1. Processed without harm

2. Blockade of critical pathways (toxicity)
Give an example of a xenobiotic that is processed without harm?
Ethanol-->Acetaldehyde-->acetate-->Acetyl CoA-->TCA (NADH, etc)
Give an example of a xenobiotic that leads to a blockade of critical pathways?
Fluoroethanol (so the addn of only one atom to ethanol)

Fluorethanol-->F-acetaldehyde-->F-acetate-->F-Acetyl-CoA-->blockade of TCA

F-acetate is actually a pesticide known as compound 1080.
What is an antedote to the blockade of TCA by fluoroacetate?
Alcohol (competitive substrate)
What is the rat LD50 for the Rodenticide Fluoroacetate (compound 1080)?
0.2mg/kg (so supertoxic range)
What is methanol and where can it be found?
Wood alcohol. Found in windshield washer fluid, fuel, after shave lotions, general solvent. This can be a cheap EtOH substitute for alcoholics.
What are the CNS effects of methanol?
Initial CNS effects are inebriation. Then blindness in primates because of formaldehyde formation in primates. Eventually death due to metabolic acidosis.

What are two antidotes for methanol?
Competitive inhibitors:

1. Ethanol (100mg/dl) (so have to make them legally drunk)

2. 4-methyl pyrazole (fomepizole)
What is the other name for 4-methyl pyrazole?
The generic name is fomepizole.
What is the potency of 4-methyl pyrazole?
8000 times more potent than EtOH as a competitive inhibitor.
Etylene glycol is ? absorbed.
Rapidly absorbed.
Ethylene glycol poisoning can lead to what?
Metabolic acidosis and Crystalluria.

1-12 hr CNS effects - no EtOH odor

12-24 hr cardiopulmonary, CHF

24-72 hr renal failure
What does 4-methyl pyrazole inhibit?
Alcohol dehydrogenase (which is an important intermediate in antifreeze poisoning and methanol poisoning, etc)
What is a lethal dose of ethanol in a human?
~14-20 drinks (350-500mg/dL)(drink = 1oz EtOH)
What are the lethal doses of Ethylene glycol in humans, dogs, and cats?
(Much more potent than ethanol)

Humans ~100mL (21mg/dL)(~1.2mL/kg)

Dogs (4mL/kg)

Cats (1.4mL/kg)
What are the lethal doses of methanol in humans and dogs?
Humans 30-240mL (80mg/dL)

Dogs ~ 90mL - 8g/kg
Describe the nomenclature of CYP2E1.
CYP = Cytochrome P450

2 = Family (>40% homology)

E = Subfamily (>55% homology)

1 = individual form (very specific enzyme)
What does CYP2E1 metabolize?
List 3 endogenous substrates?
Sterols, Fatty acids, and neurohormones.
Give an example of an exogenous substrate?
Xenobiotics, includes drugs.
What are the most active CYP families?
CYP2C, CYP2D, and CYP3A are metabolize the greates percentage of important drugs. (CYP3A is the most active of these at ~36%) (together these three make up about 75% of drug metabolism)
What are P450's responsible for?
Most drug and other xenobiotic metabolism.