Variability in Aflatoxin B1–Macromolecular Binding and Relationship to Biotransformation Enzyme Expression in Human Prenatal and Adult Liver

Abstract

Studies of transplacental transfer of aflatoxin B1 (AFB1) suggest that the developing human fetus may be a sensitive target for AFB1 injury. Because AFB1 requires metabolic activation to the reactive AFB1-8,9-exo-epoxide (AFBO) to exert its carcinogenic effects, ontogenic and interindividual differences in AFB1 biotransformation enzymes may underlie susceptibility to AFB1-induced cell injury. The present study was initiated to compare the rates of in vitro AFB1–DNA and AFB1–protein adduct formation among a panel of 10 adult and 10 second-trimester prenatal livers and to examine the relationship among AFB1 metabolizing enzyme expression and AFB1 binding. Mixtures of cytosolic and microsomal proteins from prenatal and adult livers catalyzed the formation of AFB1–DNA and AFB1–protein adducts at relatively similar rates, although greater individual variability in AFB1 adduct formation was observed in adult tissues. Extensive interindividual variation among adult tissues was observed in the expression of the AFB1 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 AFB1–DNA or AFB1–protein adduct formation and expression levels of individual AFB1 metabolizing enzymes. In summary, despite the presence of marked individual and ontogenic differences in the expression of AFB1 metabolizing enzymes, human second trimester prenatal liver tissues compared to adults do not exhibit a marked sensitivity to the in vitro formation of macromolecular AFB1 adducts.