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29 Cards in this Set

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  • Back
What is the goal of detoxification?
convert foreign compounds into a water-soluble, excretable form
What are the two phases of detoxification?
Phase I: reactions add 1+ polar functional groups to lipohilic compounds (most are oxidations)

Phase II: reactions increase water solubility by CONJUGATING the foreign substance with a polar compound
What is the main organ of detoxification?
What is unique about the enzymes in the liver?
-They have borad specificity (nonspecific)
-occur as multiple isoenzymes (enzymes that cataylze the same rxns)
-are usually inducible(not transcribed at high levels normallly, but can be induced to do so--which is energy efficient)
What is the most important detoxification enzyme in the liver?
cytochrome P450 monooxygenase system
What is dangerous about detoxification?
Some rxns result in the activation of a substance to a more toxic compound
Detoxification of a particular compound can occur with how many different pathways? And is the expression of these enzymes the same from person to person?
More than one pathway

There is considerable genetic variability in expression of detoxification enzymes
What is pharmacogenomics?
study of genetic polymorphisms that affect an individual' response to a drug
Give examples of how metabolism of one substance can alter the metabolism of another.
St. Johns Wort increases the metabolism of drugs by CYP3A4

Grapefruite inhibits the CYP3A4 which leads to an accumulation of toxic levels
Where is the highest level of P450 activity found?
Microsomal fraction of the liver
What is the net reaction of the P450 catalyzed reactions? What is unique about this reaction? And what role does P450 reductase play?

It uses molecular O2--which is rare

transfers e- from NADPH to the cytochrome
What are some characteristics of P450?
heme containing enzyme
broad specificities
18 families of cyt P450 and 57 functional genes

At least 12 different P450 isoenzymes (with different, but overlapping specificities)
How do polycyclic aromatic hydrocarbons induce cyt P450?
-bind cystolic receptor protein
-diffuse across cell membrane and bind Ah receptor
-receptor complex diffuses into nucleau and binds DNA at xenobiotic regulatory element
*permits binding of transcription factors to promoters and transcription of P450 mRNAs
Induction of P450 results in the increased synthesis of what proteins?
rRNA, ribosomal proteins, heme and phase II enzymes
What do SXR and CAR regulate?
SXR - regulates synthesis of CYP3A

CAR - regulates synthesis of CYP2B
What enzymes protect against reactive oxygen species?
What are two reactive oxygen species?
superoxide and hydrogen peroxide
What happens if superoxide and hydrogen peroxide react to each other?
form an even more reactive species
What does glutathione reductase do and what does it require?
Glutathione reductase converts glutathione back to a usable form, but it requires an NADPH
What is alcohol dehydrogenase?
oxidizes alcohol to aldehydes (which catalase and P450 also do)
What is aldehyde dehydrogenase? And what inhibits it?
group of isoenzymes that oxidize aldehydes to carboxylic acids

Disulfiram inhibits it (you will get very sick if you drink alcohol while on it--used for alcoholics)
What are the negative effects of alcohol and where do they come from?
Flush reaction (build up of aldehydes--primarily in asian population)
What are alcohols oxidized to?
aldehydes and then carboxylic acids
What are different compound used in Phase II reactions?
1. conjugation with glucuronic acid
2.conjugation with sulfate--need a reactive intermediate (PAPS)
3.conjugation with glutathione
What are all phase II reactions called?
Can a compound undergo more than one Phase II reaction?
What is the risk of converting something to be more toxic with phase II reactions?
rarely happens
How is acetaminophen normally detoxified?
it uses glucuronide, sulfide or both
What happens at high doses of acetaminophen?
The P450 pathway becomes more important--it uses the glutathione pathway and depletes it. This liver damage can be fatal.