applications of toxicogenomics

8/6/2019 Applications of Toxicogenomics

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Applications of Applications of

ToxicogenomicsToxicogenomics



Toxicology is multidispliniary fieldToxicology is multidispliniary field

It is quantitative & qualitative study of adverseIt is quantitative & qualitative study of adverseeffects of chemicals on living organismseffects of chemicals on living organismsToxicity is the adverse biological response to aToxicity is the adverse biological response to a

chemical reactionchemical reactionToxicogenomicsToxicogenomics provides valuable information on the provides valuable information on theeffects of drugs and chemicals at a molecular level,effects of drugs and chemicals at a molecular level,

providing a more complete understanding of their providing a more complete understanding of their

potential toxic effects potential toxic effects



F ollowing the law of mass action, the rate if aF ollowing the law of mass action, the rate if achemical reaction depends on concentrationschemical reaction depends on concentrationsof 2 reactants.of 2 reactants.The active toxicant and the biologicalThe active toxicant and the biologicalresponse/targetresponse/targetThe more active toxicant present, the greater isThe more active toxicant present, the greater is

the dose,the dose,More toxicity, the greater is the responseMore toxicity, the greater is the responseThis is doseThis is dose- -response relationshipresponse relationship



E xposure to a single high conc. Will elicit anE xposure to a single high conc. Will elicit animmediate (acute) response that is qualitativeimmediate (acute) response that is qualitativedifferent from repeated exposure (chronic) to thedifferent from repeated exposure (chronic) to the

same chemical at much lower conc.same chemical at much lower conc.F or ex.a single exposure to 1 mg of afatoxin BF or ex.a single exposure to 1 mg of afatoxin B 11 to ato arat, will result in killing of large numbers of liver rat, will result in killing of large numbers of liver cells and death due to liver failure within 5cells and death due to liver failure within 5- -6 days.6 days.

E xposure to few nanograms for several months doesE xposure to few nanograms for several months doesnot kill liver cells but results liver cancer not kill liver cells but results liver cancer



Dose response relationshipDose response relationship

Wide quantitative variations in drug responsesWide quantitative variations in drug responsesoccur b/w diff species and within same speciesoccur b/w diff species and within same species

with diff conditionwith diff conditionE ach drug has a characteristic response curveE ach drug has a characteristic response curvefor a specified set of conditions.for a specified set of conditions.The dose response curve forms SThe dose response curve forms S- -shaped or shaped or sigmoid type.sigmoid type.2 types of relationship2 types of relationship



2 types of relationship2 types of relationship

G raded or quantitative doseG raded or quantitative dose- -responseresponserelationshiprelationship

Quantal or quantitative doseQuantal or quantitative dose- -responseresponserelationshiprelationship



G raded or quantitative doseG raded or quantitative dose- -

response relationshipresponse relationshipThis type relates the size of the response in a singleThis type relates the size of the response in a single biological unit to the dose of the drug. biological unit to the dose of the drug.As the dose administered to a tissue is increases, theAs the dose administered to a tissue is increases, the

pharmacological response will also increase in graded pharmacological response will also increase in gradedfashion provided the dose has not exceeded thefashion provided the dose has not exceeded thethreshold dose.threshold dose.The degree of response produced by increasing theThe degree of response produced by increasing the

doses of a drug eventually reaches a steady leveldoses of a drug eventually reaches a steady leveltermed astermed as ceiling response.ceiling response.And the dose is called aAnd the dose is called a celing doseceling dose



If the dose exceed the ceiling dose, there is noIf the dose exceed the ceiling dose, there is nofuther increase in the therapeutic effect.futher increase in the therapeutic effect.

Such dose have undesirable responses.Such dose have undesirable responses.The ceiling dose allows to compare theThe ceiling dose allows to compare thetherapeutic efficacy of varioustherapeutic efficacy of various

pharmacologically active compds. pharmacologically active compds.



Q ualtal or all or none doseQ ualtal or all or none dose- -responseresponse

relationshiprelationshipThis curve shows the frequency with which any doseThis curve shows the frequency with which any doseof drug evokes a stated, fixed(all or none) response.of drug evokes a stated, fixed(all or none) response.It is a frequency distribution of the responders toIt is a frequency distribution of the responders to

different doses of drug.different doses of drug.E ach animal is categorized as responding or none.E ach animal is categorized as responding or none.In case of lethal toxicity tests, each animal isIn case of lethal toxicity tests, each animal isclassified as dead or alive at specified time after theclassified as dead or alive at specified time after the

drug treatment.drug treatment.Some animals will respond to smaller doses of drugSome animals will respond to smaller doses of drugand some are resistant and need large doses.and some are resistant and need large doses.



The sensitivity of animals to diff doses of a drug isThe sensitivity of animals to diff doses of a drug isdistributed normally with respect to the logarithm of distributed normally with respect to the logarithm of the dose.the dose.F or a given dose, if log is plotted on the horizontalF or a given dose, if log is plotted on the horizontalaxis, a gaussian(normal) distribution is obtained.axis, a gaussian(normal) distribution is obtained.The curve represents the distribution of sensitivity of The curve represents the distribution of sensitivity of

a group of animals to the given drug.a group of animals to the given drug.The curve«.The curve«.



The quantal dose response curve will notThe quantal dose response curve will notalways bellalways bell- -shaped.shaped.

But may show skewing or truncation.But may show skewing or truncation.This shows that inter This shows that inter- -coupled events andcoupled events andexperimental limitations influence the quantalexperimental limitations influence the quantaldose response curve.dose response curve.



The median lethal dose or L DThe median lethal dose or L D 5050

This is the dose(mg/kg) which would beThis is the dose(mg/kg) which would beexpected to kill oneexpected to kill one- -half of an unlmitedhalf of an unlmited

population of the same species and strain. population of the same species and strain.



M argin of safetyM argin of safety

It is the difference between the therapeutic and lethalIt is the difference between the therapeutic and lethaldose of a drug.dose of a drug.As the drug metabolism varies from species toAs the drug metabolism varies from species tospecies, the therapeutic index will also vary.species, the therapeutic index will also vary.The larger the therapeutic index the safer is the drug.The larger the therapeutic index the safer is the drug.F or safe therapeutic application, the TI must be moreF or safe therapeutic application, the TI must be more

than one.than one.Such drugs will have v.little doseSuch drugs will have v.little dose- -related toxicity.related toxicity.



The TI gives only a rough idea about theThe TI gives only a rough idea about thesafety.safety.

Depending upon its clinical use, a drug mayDepending upon its clinical use, a drug mayhave many TI.have many TI.E g. The margin of safety of aspirin if used for E g. The margin of safety of aspirin if used for headache is far greater than its margin of headache is far greater than its margin of safety of athritic pain or rhematic fever,safety of athritic pain or rhematic fever,This is because the latter required larger dose.This is because the latter required larger dose.

applications of toxicogenomics

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