Determination of aflatoxin B-1 biotransformation and binding to hepatic macromolecules in human precision liver slices

Although epidemiological studies suggest that aflatoxin B-1 (AFB(1)) is a human carcinogen, at least in the presence of hepatitis B virus infection, animal studies have demonstrated large differences in species sensitivity to AFB(1), and the sensitivity of humans relative to experimental animals remains unclear. The purpose of this study was to determine the profile of AFB(1) metabolism and the extent of AFB(1) binding to cell macromolecules in human liver slices under experimental conditions that would allow direct comparison to similar endpoints in the rat, a species sensitive to the carcinogenic actions of AFB(1). Liver slices were prepared from three individual human liver samples with a Krumdieck tissue slicer and incubated with 0.5 mu M [H-3]AFB(1) for 2 hr. Significant interindividual variations were observed in the rates of oxidative metabolite formation and in specific binding to cell macromolecules. The rates of oxidative metabolism of AFB(1) to AFQ(1), AFP(1), and AFM(1) in the three human liver samples were similar to those previously observed in rat liver slices. AFB(1)-GSH conjugate formation was not detected in any of the human liver samples, and yet specific binding of AFB(1) to cell macromolecules was considerably lower in the human liver slices relative to that in rat liver slices. AFB(1)-DNA binding levels ranged from 3 to 26% of control rat and AFB(1)-RNA binding levels ranged from 25 to 49% of control rat. The AFB(1)-protein binding level in the one human sample measured was 20% of that observed for control rat. While these results suggest that humans do not form as much AFBO as the rat, they are also consistent with the hypothesis that humans do not possess GST isozyme(s) with high specific activity toward AFBO. Significant individual differences in AFB(1) metabolism and binding between humans suggest the presence of genetic and/or environmental factors that may confer large variability in susceptibility to AFB(1). (C) 1996 Academic Press, Inc.