DNA binding and mutagenicity of aflatoxin B1 catalyzed by isolated rabbit lung cells

The abilities of different rabbit lung cell types to bioactivate aflatoxin B1 (AFB1) to a DNA-binding and mutagenic metabolite have been examined. Microsomes were prepared from centrifugal elutriation-enriched preparations of isolated rabbit lung cell types. The activation of [3H]AFB1 (5.0 or 200 microM), measured indirectly as covalent binding to calf thymus DNA, was concentrated in microsomes from the non-ciliated bronchiolar epithelial (Clara) cell-rich fractions (13-22 times the activity of whole lung microsomes). Microsomes from type II cell-rich fractions had minimal activity. Significant correlations were detected between the rates of microsomal DNA binding and the percentages of Clara cells in the fractions. Prior treatment of rabbits with the cytochrome P450 class 1A inducer beta-naphthoflavone had no significant effect on the microsomal activation of AFB1. In other experiments, intact, enriched isolated rabbit lung cells were incubated with AFB1 (0-1.5 microM) in a modification of the Ames mutagenicity assay, using Salmonella typhimurium strain TA100. The ability to activate AFB1 to mutagenic metabolite(s) in this system was localized in Clara cell-rich fractions, with no significant activity being detected in other fractions. The results of these studies indicate that the biotransformation of AFB1 to DNA-binding and mutagenic metabolite(s) in rabbit lung is heterogeneous, and that the Clara cell is specifically implicated in this ability.