LMP299Y1 Lecture Notes - Lecture 18: Acetyl-Coa, Ethanol Metabolism, Acetaldehyde Dehydrogenase
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Published on 12 May 2015
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Lecture'18'–'toxicology''
Objectives'
" Understand!biotransformation!
" Understand!phase!I!and!II!metabolism!of!toxins!
" Tie!in!other!lectures!to!understand!how!toxins/metabolites!contribute!to!liver!pathology!
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Toxicology'has'been'defined'as…'
" “The!study!of!the!adverse!effects!of!xenobiotics”!
" Concerned!with!understanding!the!mechanisms!of!action!and!exposure!to!chemicals!as!a!cause!of!acute!and!
chronic!illness.”!
" Xenobiotics!=!pharmacologically!active!substance!that!is!not!endogenously!produced!by!the!organism!
" Many!branches!of!toxicology!
o Clinical!toxicology!→!why!is!the!patient!unconscious!in!ED!
o Forensic!toxicology!
o Environmental!toxicology!
o Public!health!and!safety!
o Molecular!toxicology!
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Similarities'between'toxicology'and'TDM'(therapeutic!drug!monitoring)!→!one!level!is!
therapeutic!other!is!toxic!!
" Pharmacokinetics!→!how!body!deals!with!the!drug!
" Pharmacodynamics!→!how!drug!itself!influences!the!body!through!receptors!–!both!
TDM!and!toxins!–!in!return,!the!body!tries!to!eliminate!both!because!it!is!foreign!so!it!
tries!to!rid!itself!from!it!
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Liver'role'in'biotransformation'(metabolism)'of'toxins'
" Biotransformation!is!the!process!of!converting!lipophilic!(fat!soluble)!chemicals!into!hydrophilic!(water!soluble)!
chemicals,!which!are!readily!excreted!into!urine!or!bile!
o Trying!to!alter!the!chemistry!of!the!drug!to!inactive!it…!sometimes!drugs!such!as!Tylenol!produces!a!very!
toxic!metabolite!instead!of!an!inactive!metabolite!so!sometimes!it!fails!but!body!still!has!mechanism!that!
deals!with!it!
o Trying!to!make!it!more!water!soluble!so!it’s!more!easily!excreted!
" Biotransformation!alters!the!biological!properties!of!xenobiotics!so!that!it!is!less!toxic!(detoxification).!However,!in!
some!cases!it!can!produce!a!more!toxic!metabolite!(example:!EtOH)!
" Biotransformation!is!catalyzed!by!various!enzymes!that!can!be!divided!into!4!categories!(based!on!their!reaction):!
o Hydrolysis!
o Reduction!
o Oxidation*!
o Conjugation!(examples:!gluuronidation,!sulfonation)!
" Many!enzymes!involved!in!biotransformation/metabolism!are!known!to!be!genetically!polymorphic;!as!a!result,!
the!activity!of!these!enzymes!may!vary!among!individuals!in!the!population!
" Exposure!to!xenobiotics!is!largely!through!oral!ingestion!(but!it!is!not!limited!to!this!route!or!transmission).!As!a!
result,!the!small!intestine!and!liver!play!an!active!role!in!limiting!exposure!to!orally!ingested!xenobiotics!(1st!pass!
metabolism)!
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Phase'I'
" Inactivation!of!compounds!→!drug!enters!body!through!oral!ingestion,!dermal!(gases)!into!
blood!stream!→!body’s!first!response!is!to!try!and!inactive!the!compound!
" Changes!pharmacological!activity!→!hopefully!making!it!less!toxic!
" Occurs!primarily!in!the!liver*!
" Involves!the!cytochrome!P"450!system!(examples:!oxidation,!reduction,!hydrolysis!rxn’s)!
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" P"450!enzymes!are!clustered!in!the!mitochondria!and!goes!through!reaction!
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Step'1!–!Cytochrome!P"450!enzyme!with!iron!molecule!in!the!middle!–!it’s!in!an!oxidized!state!(Fe3+)!and!that!
forms!a!site!the!drug!can!bind!to!and!it!bind!to!the!nitrogen!atom!on!the!enzyme!–!in!a!planar!mode!–!as!drug!
binds!to!it,!enzyme!change!conformation!–!part!of!the!molecule!goes!down,!exposing!the!drug!on!top!
Step'2!–!P"450!reductase!enzyme!transfers!the!electron!to!the!Fe3+!and!reduces!it!to!Fe2+!
Step'3!–Oxygen!comes!on!and!it’s!also!catalyzed!by!a!P"450!–!it!forms!a!peroxide!dianion!–!this!allows!the!
binding!of!two!protons!to!it!and!the!binding!of!these!two!protons!causes!a!conformational!change!that!places!
an!electron!onto!the!drug!itself!becomes!oxidized!and!hopefully!alters!the!pharmacological!activity!of!it!and!
also!produces!a!molecule!of!water!and!brings!back!Fe3+!so!it!can!go!through!the!cycle!again!
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Phase'II'
" Conjugation!reactions!(glucuonic!acid,!sulfate,!glycine,!glutathione)!
" Occurs!in!the!kidneys!and!liver*!
" Enhances!excretion!of!drugs!by!making!the!compound!
more!water!soluble!
" Ultimate!effect!is!to!facilitate!elimination!!
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" For!example!the!glucuronidation!of!bilirubin!
" Alpha"glucuronic!acid!goes!through!mechanism!of!beta"
glucuronidase!and!converts!it!to!a!glucuronoid!then!
UDP"glucuronyltransferase!then!takes!for!example!
morphine,!and!converting!it!to!a!morphine"3"
glucuronoid!then!to!morphine"6"glucuronoid!–!making!it!
more!water!soluble!then!through!kidneys!and!finally!
excreted!
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Elimination'of'drugs/toxins'
" Most!important!route!is!the!kidney!
o Glomerular!filtration!
o Active!tubular!secretion!
" May!also!involve!secretion!of!drug!into!bile!(excreted!via!intestine)!
" Other!routes:!breath,!breast!milk,!saliva!(secondary)!!
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Summary'of'metabolism'and'elimination'of'drugs/toxins'
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Phase I
P450 Class of Enzymes