Evaluation of the effects of a VEGFR-2 inhibitor compound on alanine aminotransferase gene expression and enzymatic activity in the rat liver.docVIP

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Evaluation of the effects of a VEGFR-2 inhibitor compound on alanine aminotransferase gene expression and enzymatic activity in the rat liver.doc

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Evaluation of the effects of a VEGFR-2 inhibitor compound on alanine aminotransferase gene expression and enzymatic activity in the rat liver

Fuentealbaetal.ComparativeHepatology2011,10:8 /content/10/1/8 RESEARCH OpenAccess EvaluationoftheeffectsofaVEGFR-2inhibitor compoundonalanineaminotransferasegene expressionandenzymaticactivityintheratliver CarmenFuentealba1,2*,MonaliBera2,BartJessen1,FredSace1,GregJStevens1,DuskoTrajkovic1,AmyHYang1 andWinstonEvering1 Abstract Background:Traditionalassessmentofdrug-inducedhepatotoxicityincludesmorphologicalexaminationofthe liverandevaluationofliverenzymeactivityinserum.Theobjectiveofthestudywastodeterminetheoriginof drug-relatedelevationinserumalanineaminotransferase(ALT)activityintheabsenceofmorphologicchangesin theliverbyutilizingmolecularandimmunohistochemicaltechniques. Methods:SixteenfemaleSprague-Dawleyratsweredividedinto2groups(controlandtreated,n=4pergroup) andtreatedratsweredosedorallytwicedaily(400mg/kg/day)for7dayswithaVEGFR-2compound(AG28262), whichinapreviousstudycausedALTelevationwithoutmorphologicalchanges.Serumofbothtreatedand controlanimalswereevaluatedonday3oftreatmentandatday8.Threeseparateliverlobes(caudate,right medial,andleftlateral)wereexaminedfordeterminationofALTtissueactivity,ALTgeneexpressionand morphologicalchanges. Results:ALTactivitywassignificantly(p0.01)elevatedonday3andfurtherincreasedonday8.Histologic changesorincreaseinTUNELandcaspase3positivecellswerenotobservedintheliverlobesexamined.ALTgene expressioninthecaudatelobewassignificantlyup-regulatedby63%.ALTexpressionintheleftlaterallobewas notsignificantlyaffected.StatisticallysignificantincreasedliverALTenzymaticactivityoccurredinthecaudate (96%)andrightmedial(41%)lobesbutnotintheleftlaterallobe. Conclusions:AG28262,aVEFG-r2inhibitor,causesanincreaseinserumALT,dueinparttobothgeneup- regulation.Differencesbetweenliverlobesmaybeattributabletodifferentialdistributionofbloodfromportal circulation.Incorporationofmoleculardata,suchasgeneandproteinexpression,andsamplingmultipleliverlobes mayshedmechanisticinsighttotheevaluationofhepatotoxicity. Keywords:Drugsafety,hepatotoxicity,liveren