title: Variability in aflatoxin B(1)-macromolecular binding and relationship to biotransformation enzyme expression in human prenatal and adult liver.
abstract: Studies of transplacental transfer of aflatoxin B(1) (AFB(1)) suggest that the developing human fetus may be a sensitive target for AFB(1) injury. Because AFB(1) requires metabolic activation to the reactive AFB(1)-8,9-exo-epoxide (AFBO) to exert its carcinogenic effects, ontogenic and interindividual differences in AFB(1) biotransformation enzymes may underlie susceptibility to AFB(1)-induced cell injury. The present study was initiated to compare the rates of in vitro AFB(1)-DNA and AFB(1)-protein adduct formation among a panel of 10 adult and 10 second-trimester prenatal livers and to examine the relationship among AFB(1) metabolizing enzyme expression and AFB(1) binding. Mixtures of cytosolic and microsomal proteins from prenatal and adult livers catalyzed the formation of AFB(1)-DNA and AFB(1)-protein adducts at relatively similar rates, although greater individual variability in AFB(1) adduct formation was observed in adult tissues. Extensive interindividual variation among adult tissues was observed in the expression of the AFB(1) activation enzymes cytochrome P4501A2 (CYP1A2), CYP3A4/5, and lipoxygenase (LO). Prenatal CYP3A7 expression was also highly variable. LO expression was eightfold higher in prenatal liver tissues than adults, whereas the expression of the AFBO detoxification enzyme microsomal epoxide hydrolase was twofold higher in adult liver. The levels of the polymorphic glutathione S-transferase M1 (hGSTM1-1), which may potentially protect against AFBO injury, were higher in the hGSTM1-1-expressing tissues of adults in relation to prenatal livers. In general, there was not a strong relationship among AFB(1)-DNA or AFB(1)-protein adduct formation and expression levels of individual AFB(1) metabolizing enzymes. In summary, despite the presence of marked individual and ontogenic differences in the expression of AFB(1) metabolizing enzymes, human second trimester prenatal liver tissues compared to adults do not exhibit a marked sensitivity to the in vitro formation of macromolecular AFB(1) adducts.
authors.affiliation: Department of Physiological Sciences, University of Florida, Gainesville, Florida 32611, USA.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Doi
authors.forename: Paula E
authors.initials: PE
authors.lastname: Patterson
authors.forename: Evan P
authors.initials: EP
authors.lastname: Gallagher
mesh_terms: D016604:Aflatoxin B1 / Q000493:pharmacokinetics*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D004798:Enzymes / Q000378:metabolism; D005333:Fetus; D005865:Gestational Age; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008084:Lipoxygenase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018736:DNA Adducts; D004798:Enzymes; D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D008084:Lipoxygenase