biotransformation. this is the part of forensic toxicology

forensic toxicology

1. BIOTRANSFORMATION
OF
XENOBIOTICS

2. BIOTRANSFORMATION OF XENOBIOTICS
•Innature,theorganismsareoftenexposedtoawide
varietyofchemicals,whichareforeigntotheirbody.
•Ofthese,thelipophilicsubstanceseasilypenetrate
thelipoproteinbilayersoftheircellmembranesand
finallyreachthetargetcells.
•Ifsuchchemicalsarecontinuouslyorintermittently
exposedtoorganismsandaregraduallyabsorbedby
theorganismsbutnoteliminatedfromtheirbody,
theytendtoaccumulate.
•Thus,theymayproducelethaleffects.

3. BIOTRANSFORMATION OF XENOBIOTICS cont’d
•However,quiteoftenduringthecourseoftheir
transport,theypassthroughcertaintissues/organs
(suchas,liver)havingsomeactivityagainstthose
xenobiotics.
•Consequently,thelipophilicchemicalsare
biocatalyticallyconvertedintotheirhydrophilicforms
thatareeasilyexcretedfromthebodyoforganisms.
•Thebiologicallycatalyzedconversionofoneformof
xenobioticcompoundintoanotherformmaybe
simplytermedasbiotransformation.

4. BIOTRANSFORMATION versus METABOLISM
•Almostallbiochemicalreactionsinthebiological
systemtakeplaceundertheinfluenceofcertain
enzymesandthebiologicalconversionofone
compoundintoanotheristermedasmetabolism.
•Butthetermbiotransformationisusedpreferablyto
denotethebiologicalconversionofxenobioticsand
metabolismisreferredtothebiologicalconversionof
usefulandendogenoussubstances,suchasnutrients
orbodyconstituents,i.e.carbohydrates,fats(lipids),
proteins,nucleic-acids,etc.

5. PURPOSE OF BIOTRANSFORMATION
-Detoxifyharmfulsubstances.
-Facilitatetheireliminationfromthebody
-Convertthemintometabolitesthataremorewater
solubleandlesstoxic,makingthemeasiertoexcretevia
urineorbile
Inotherwords,itmaybestatedthatthebiotransformation
areoftenprerequisitestotheexcretionofxenobiotics.

6. SITES FOR BIOTRANSFORMATION
•Liver
•Intestines
•Lungs
•Kidneys
•Skin
•Brain
•Placenta

8. EFFECTS OF BIOTRANSFORMATION OF DRUGS IN THE SYSTEM
•Thebiotransformationofonexenobioticcompound
intoanotherofteninvolvesseveralchangesinthe
parentcompound.
•Thesechangesmayoccurthroughaseriesofsequential
reactionsleadingtooneormoreproducts.
•Thenewcompoundhasdistinctphysicalandchemical
properties,hencedifferentpharmacologicaland
toxicologicalproperties.

9. EFFECTS OF BIOTRANSFORMATION OF DRUGS IN THE SYSTEM
•Thus,biotransformationmayleadtofollowingalterationsinthe
toxicologicalpropertiesofthexenobiotics:
i.Enhanceorlowertheharmfuleffects.
ii.Makeaninnocuouscompoundharmful.
•Thechangescanbemadethrough:
✓Conversion of an inactive chemical into another active chemical
✓Conversion of an active chemical into another inactive chemical
✓Conversion of an active chemical into another active chemical
✓Conversion of an inactive chemical into another inactive
chemical.

10. EFFECTS OF BIOTRANSFORMATION OF DRUGS IN THE SYSTEM
•Fromtheexamplesofabovefourtypesofreactions:
✓itisobviousthatalthoughthebasicpurposeof
biotransformationreactionsisinactivationor
detoxificationofpotentxenobioticcompoundsto
facilitatetheireliminationfromthebodyoforganisms;
✓Sometimes,thebiotransformationmayalsoleadtothe
conversionofinactiveorlessactivechemicalsinto
moreactiveproducts,whicharenoteasilyexcreted
andthus,highlytoxic.

11. EFFECTS OF BIOTRANSFORMATION
OF DRUGS IN THE SYSTEM
•Although the biotransformation of foreign compounds is
often regarded as a detoxication process, this is not
always the case.
•Metabolites or intermediates may sometimes be
produced, which are more toxic than the parent
compound.
•These may be the result of phase 1, or 2 reactions,
although phase1 reactions are the most commonly
involved.

12. EFFECTS OF BIOTRANSFORMATION OF DRUGS IN THE
SYSTEM
•Theintermediatesormetabolitesresponsibleforthe
toxicitymaybechemicallyreactiveorstable.
•Whenthemetabolicprocessproducesametabolite,
whichischemicallyreactive,thisprocessisknownas
metabolicactivationorbioactivation.
•Theexactchemicalreactivitymightindeedbecrucial,
andtheremaybeanoptimumlevelforthisreactivity.
•Thus,metabolismcanunderliethetoxicityofa
compound.

14. TOXICATION VS DETOXICATION
•It is often the case that there
are several metabolic pathways
available for a foreign
compound.
•Some of these pathways could
be
i.detoxication pathways,
while others might lead to
ii.toxicity.

15. The various possible consequences of
metabolism of a foreign compound.
•Thecompoundmayundergo
detoxication(2);
•metabolicactivation(3),whichleads
tointeractionwithcriticaltargets(6)
andmaycausetoxiceffects(8;A).
•Alternatively,theparentcompound
mightcauseadirecttoxiceffect(1;B).

17. The various possible consequences of
metabolism of a foreign compound.
•FormationofaStablemetabolite(7)could
causeatoxiceffect(9;C).
•Thestablemetabolitecouldbefurther
metabolizedtoatoxicmetabolite(10)
responsibleforadifferenttoxiceffecttoC.
•Thereactivemetabolitemaybedetoxified
(4/5).
•Thetypesoftoxiceffectcausedbythe
metaboliteswouldbeoneormoreofthe
varioustypesshown.

19. EFFECTS OF XENOBIOTICS ON TISSUES
•Theeffectsofxenobioticsontissuescanbewide-
ranginganddependonthespecificsubstance,itsdose,
durationofexposure,andtherouteofentryintothe
body.
•Outlinedbelowaresomeoftheeffectsofxenobiotics
onvarioustissues:
•Toxicity
•Carcinogenicity
•Mutagenicity
•Teratogenicity

20. EFFECTS OF XENOBIOTICS ON TISSUES
1.Toxicity
-referstothedegreetowhichasubstancecanharmhumansor
animals.
-Itencompassesawiderangeofadverseeffectsthatasubstance
canhaveonlivingorganisms,dependingonvariousfactorssuchas
thedose,durationofexposure,routeofexposure,andindividual
susceptibility.
-EXAMPLESOFSPECIFICTOXICEFFECTS
•Cardiotoxicity:Somexenobioticscanharmtheheart.
•Nephrotoxicity:Kidneydamageduetoxenobioticexposure.
•Neurotoxicity:Alterednervoussystemfunction.
•Hepatotoxicity:Liverdamagecausedbyxenobiotics.

21. EFFECTS OF XENOBIOTICS ON TISSUES
2.Carcinogenicity
•referstotheabilityortendencyofasubstanceto
causecancer.
•Cancerisagroupofdiseasescharacterizedbythe
uncontrolledgrowthandspreadofabnormalcells.
•Carcinogenicsubstances,knownascarcinogens,can
induceorpromotethisabnormalcellgrowth,leading
tothedevelopmentoftumors.
•Certainmetalslikearsenic,cadmium,andchromium
arecarcinogenic.

22. EFFECTS OF XENOBIOTICS ON TISSUES
3.Mutagenicityreferstotheabilityofachemical
substanceorphysicalagenttocausemutationsinthe
DNAofanorganism.
•Mutationsarechangesinthegeneticmaterialthat
canleadtoalterationsinthestructureandfunction
ofproteins,potentiallyresultinginvariousbiological
effects,includingcancerandgeneticdisorders.

23. EFFECTS OF XENOBIOTICS ON TISSUE
4.Teratogenicityreferstotheabilityofasubstanceto
causedevelopmentalmalformations(birthdefects)in
adevelopingembryoorfetus.
•Teratogenscandisruptthedevelopmentofanembryo
orfetusbyinterferingwithcellgrowth,
differentiation,andorganformation,leadingto
structuralorfunctionalabnormalities.

24. FACTORS AFFECTING
BIOTRANSFORMATION OF XENOBIOTICS
•Itisobviousthatbiotransformationofxenobioticsmaytakeplace
bydifferentpathwaysinvolvingphaseIandIIreactionsandthey
maygiverisetodifferentbiotransformationproducts.
•Variousfactorsrelatedtotheenvironmentandthephysiological
statechemical,oforganismsaffecttherateandrelativeimportance
ofbiotransformationreactionsofxenobiotics.
•ThesefactorscanthusbedividedintoTWObroadgroups
1.Internal(physiologicalandPathological)
2.External(EnvironmentandDiet)

25. A. INTERNAL
(PHYSIOLOGICAL AND PATHOLOGICAL)

26. 1. AGE
•Thedrugmetabolicrateinthedifferentagegroupdiffers
mainlyduetovariationsintheenzymecontent,enzyme
activityandhemodynamics.
•Inneonates(uptotwomonths)andininfants(2monthsto
oneyear),themicrosomalenzymesystemisnotfully
developed.
•So,manydrugsaremetabolizedslowly.
•Forexamplescaffeinehasahalf-lifeoffourdaysinneonates
incomparisontofourhoursinadults(neonateswithdifficult
breathingaregivencaffeinetoregulatetheirbreathingby
stimulatingthepartsofthebrainthatsignalthelungsto
inflate).

27. 1. AGE cont’d
•Children(between1-12years)metabolizeseveraldrugs
muchmorerapidlythanadultsastherateofmetabolism
reachesamaximumsomewherebetween6monthsand12
years.
•Asaresult,theyrequirelargedosesincomparisontoadults
•Inelderlypeople,theliversizeisreduced,themicrosomal
enzymeactivityisdecreasedandhepaticbloodflowalso
declinesasaresultofreducedcardiacoutput,allofwhich
contributetodecreasedmetabolismofdrugs.
•Therefore,theyrequirelowerdoses.

28. 2. SEX
•Therateofbiotransformationofxenobioticsvariesaccordingtosexof
organisms.
•Gender-wisedifferencesinbiotransformationofxenobioticsbymammalian
liverappearwiththeonsetofpubertyandareusuallymaintained
throughouttheadultlife.
•Meagerstudiesofsexdependentbiotransformationinhumanshaveshown
thatfemaleshaveabettertendencyforoxidativemetabolismratesthan
themales.
•Estrogenandprogesterone,hormonesprominentinwomen,canmodulate
theexpressionandactivityofcertaindrug-metabolizingenzymes,suchas
theCytP450(CYP)family.
•Thedifferencesinbiotransformationofxenobioticsbetweenmalesand
femalesmaybeascribedtodifferentialactivityofmicrosomalenzymes,
whicharenormallyundercontrolofsexhormones.

29. 3. SPECIES DIFFERENCE
•Speciesdifferenceaffectstherateofdrugmetabolismduetothe
qualitativeandquantitativevariationsintheenzymeandtheiractivityin
thespecies.
•Qualitativedifferencesamongspeciesgenerallyresultfromthepresence
orabsenceofspecificenzymesinthosespecies.
•Quantitativedifferenceresultfromvariationintheamountand
localizationofenzymestheamountofnaturalinhibitors,andthe
competitionofenzymesforspecificsubstrates.
•HumanlivercontainslesscytochromeP-450pergramoftissuethanthe
liversofotherspecies.
•Forexample,ratlivercontainsapproximately30-50nmol/gofcytochrome
P-450,whereashumanlivercontain10-20nmol/g;furthermorehuman
liveris2%ofbodyweight,whereasratliveris4%ofbodyweight.

30. 4. HEALTH
•HealthThehealthstatusoforganismsaffectsthebiotransformation
ofxenobiotics.
•Itisobviousfromthepreviousaccountsthattheliverismost
importantorganandthesiteofbiotransformationofxenobiotics.
•Anytypeofdamage(eitherduetocertaininfectionsorduetothe
actionofchemicals)mayhavepronouncedeffectsonthelevelsof
xenobioticbiotransformingenzymesystems,hencethe
biotransformationofxenobiotics.
•Hepatitispatientshavebeenreportedtoshowimpairedabilityto
biotransformxenobioticsviamicrosomalmixedfunctionoxidase
system.

31. 5. GENETIC POLYMORPHISM
•Geneticpolymorphismreferstotheinheriteddifferencesinenzyme
structureamongindividuals,groupsorpopulationthatalterstheway
inwhichdrugsaremetabolizedinthebody.
•Thesegeneticvariationscanoccuringenesencodingdrug-
metabolizingenzymes,drugtransporters,anddrugtargets.
•EG.,IndividualswithcertainCYP2D6polymorphismsmaybepoor
metabolizersofdrugslikecodeine,affectingtheirefficacyandriskof
sideeffects.
•InthecaseofthecytochromeP450system,variationscanoccurinup
to30%ofpeopledependingontheirethnicbackground

32. B. EXTERNAL
( ENVIRONMENTAL AND DIET)

33. ENVIRONMENTAL FACTORS
•Invitroeffectsoflight,temperature,etc.on
xenobioticbiotransformationenzymesaresimilarto
thoseofotherenzymes.
•Severalenvironmentalagentsinfluencedrug
metabolizingabilityofenzymes.
•Forexample,halogenatedpesticides,cigarettesmoke,
insecticides,heavymetalsandsoon.

34. a. DIET
-Nutrientintakecaninfluencetheactivityofmetabolic
enzymes.
-Adequatenutritionsupportsliverandkidney
function,aidingintoxicantexcretion.

35. 2. DIET cont’d
•Theenzymecontentandactivityarealteredbyanumberof
dietarycomponents.
•Certainfoodsmayinduceorinhibitspecificmetabolicpathways
•Generally;
➢Lowproteindietdecreasesandhighproteindietincreasesthe
drugmetabolizingabilityasenzymesynthesisispromotedby
proteindietandalsoraisesthelevelofaminoacidfor
conjugationwiththedrugs.
➢Fatfreedietdepressescytochromep-450levelssince
phospholipids,whichareimportantcomponentsofmicrosomes
becomedeficient.