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29 Cards in this Set
- Front
- Back
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What is the goal of detoxification?
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convert foreign compounds into a water-soluble, excretable form
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What are the two phases of detoxification?
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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 |
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What is the main organ of detoxification?
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Liver
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What is unique about the enzymes in the liver?
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-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) |
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What is the most important detoxification enzyme in the liver?
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cytochrome P450 monooxygenase system
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What is dangerous about detoxification?
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Some rxns result in the activation of a substance to a more toxic compound
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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?
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More than one pathway
There is considerable genetic variability in expression of detoxification enzymes |
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What is pharmacogenomics?
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study of genetic polymorphisms that affect an individual' response to a drug
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Give examples of how metabolism of one substance can alter the metabolism of another.
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St. Johns Wort increases the metabolism of drugs by CYP3A4
Grapefruite inhibits the CYP3A4 which leads to an accumulation of toxic levels |
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Where is the highest level of P450 activity found?
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Microsomal fraction of the liver
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What is the net reaction of the P450 catalyzed reactions? What is unique about this reaction? And what role does P450 reductase play?
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NH+O2+NADPH -->ROH+H20+NADP
It uses molecular O2--which is rare transfers e- from NADPH to the cytochrome |
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What are some characteristics of P450?
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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) |
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How do polycyclic aromatic hydrocarbons induce cyt P450?
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-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 |
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Induction of P450 results in the increased synthesis of what proteins?
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rRNA, ribosomal proteins, heme and phase II enzymes
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What do SXR and CAR regulate?
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SXR - regulates synthesis of CYP3A
CAR - regulates synthesis of CYP2B |
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What enzymes protect against reactive oxygen species?
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Glutathione
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What are two reactive oxygen species?
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superoxide and hydrogen peroxide
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What happens if superoxide and hydrogen peroxide react to each other?
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form an even more reactive species
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What does glutathione reductase do and what does it require?
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Glutathione reductase converts glutathione back to a usable form, but it requires an NADPH
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What is alcohol dehydrogenase?
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oxidizes alcohol to aldehydes (which catalase and P450 also do)
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What is aldehyde dehydrogenase? And what inhibits it?
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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) |
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What are the negative effects of alcohol and where do they come from?
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Flush reaction (build up of aldehydes--primarily in asian population)
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What are alcohols oxidized to?
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aldehydes and then carboxylic acids
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What are different compound used in Phase II reactions?
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1. conjugation with glucuronic acid
2.conjugation with sulfate--need a reactive intermediate (PAPS) 3.conjugation with glutathione |
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What are all phase II reactions called?
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transferases
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Can a compound undergo more than one Phase II reaction?
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yes
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What is the risk of converting something to be more toxic with phase II reactions?
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rarely happens
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How is acetaminophen normally detoxified?
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it uses glucuronide, sulfide or both
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What happens at high doses of acetaminophen?
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The P450 pathway becomes more important--it uses the glutathione pathway and depletes it. This liver damage can be fatal.
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