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Topic 10.docx

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HLTH 340
Steve Mc Coll

Topic 10: Toxicokinetics - Metabolism Part 3 Phase-2 metabolism (conjugation)  What happens in Phase 2 metabolism? Discuss. o Recall that Phase-2 metabolism enzymes (in SER or cytosol) attach conjugating group -- i.e. we are attaching something to the molecule  Notably, this works both with lipophilic xenobiotics (i.e. something that Phase 1 didn't touch) and their Phase-1 metabolites (something that Phase 1 did touch) o The only requirement is for available oxygenated functional groups (often from Phase-1 reaction)  i.e. R-OH, R-COOH, R>O  What is the result of Phase 2 metabolism? Discuss. o Phase-2 reactions convert lipophilic compounds to hydrophilic metabolites  This is because (as suggested above), it attaches conjugating group -- which notably is anionic (negative charge) o As a result, there is ready excretion of hydrophilic conjugates by glomerular ultrafiltration in kidney  Recall that it is passive -- no energy required  However, this means that it is first-order excretion kinetics (slow)  How is Phase 2 metabolism related to biliary excretion? (since we have already discussed renal excretion) o Phase 2 metabolism affects the effectiveness of biliary excretion, because if it is conjugated hydrophiles in the bile that gets sent into GI tract, it prevents later gut reabsorption  Because if they were not conjugated and still lipophilic, they could just come back o However, notably, bacterial enzymes in large intestine may remove conjugating groups by hydrolysis Phase-1 and Phase-2 metabolism often work in tandem process to enable elimination of drugs and xenobiotics  Explain the different pathways within this mechanism. o One pathway is when drugs by-pass phase I and go straight to phase 2, which leads to conjugation and subsequent elimination/excretion o Another group of pathways is when drugs lack functional groups:  Thus Phase 1 could functionalize it and thereby modify but not suppress its activity, after which it would get conjugated in Phase 2 and eliminated  Or the result of Phase 1 metabolism could be the formation of an inactive drug metabolite o Lastly, a drug could bypass both Phase 1 and 2 and get eliminated (i.e. no functionalization or conjugation necessary) o Note that the general trend is that we take lipophilic compounds and progressively make them more hydrophilic (once they are hydrophilic, they can be eliminated) With that last point in mind, explain why hydrophilic substances are generally  advantageous o Most (not all) conjugating reactions are classified as detoxification reactions o Very few phase 2 conjugation reactions actually bioactivate substances o Another advantage is, they restrict distribution to target tissues Phase-1 and Phase-2 metabolism of phenacetin and acetaminophen  Discuss the relationship of phenacetin and acetaminophen. o Firstly it should be noted that they are both pain-killers, but phenacetin is an inactive form of acetaminophen -- it must be converted via Phase 1 metabolism to acetaminophen in the liver and only then is it active  Whereas acetaminophen is immediately active o The conversion reaction is facilitated by the CYP 2E1 enzyme, and it results in a hydroxyl group on the aromatic ring instead of an O-Et group  Notably, this means that the activation reaction is an O-dealkylation reaction  Also note that the hydroxyl group makes it only slightly hydrophilic and a very weak acid o So at this point, we have acetaminophen and it undergoes a second step (phase 2 metabolism) in the liver called glucoroniation  Here the OH group is replaced with O-glucoronide, and it is negatively charged which means it is very hydrophilic  Now it is a "strong weak acid" (?) and is readily excretable Several classes of Phase-2 conjugating groups - 3 types are important in humans  Alright, so we have conjugation reactions that can happen…awesome. What are the unique components of each reaction which will together determine what actually happens? o Well firstly, each conjugation group has a specific cofactor: this provides conjugating group and energy to make conjugation reaction proceed  Often when we think energy, we have NADPH…it provides energy and also acts like a shuttle to carry stuff across the cell o Also there is a transferase enzyme: it specifically catalyzes each type of conjugation reaction  Of course there are many subtypes within enzymes or isoforms) -- these have different substrate preferences, may create different products  What are the 3 classes of conjugating groups which we will discuss? Expound on each. o Glucuronyl transferase (GST), sulfotransferase, and glutathion-S-transferase (GST) o Glucuronyl transferase (GT) adds a glucose-derived carboxy sugar ( COO-, a weak acid)  Sample reactions:  UDP-glucuronic acid + R-OH --/GT/--> UDP + R-O- glucuronide- (easily excreted)  UDP-glucuronic acid + R-NH --/GT/--> UDP + R-NH-
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