Bacterial mutagenicity of selected procarcinogens in the presence of recombinant human or rat cytochrome P4501A1.

Cytochrome P4501A1 (CYP1A1) is an important enzyme of procarcinogen activation. We have studied bacterial (Ames test) mutagenicity resulting from mutagen activation by recombinant human or rat CYP1A1. Mutagenicity depends on both the chemical group and species-specific activation: polycyclic aromatic hydrocarbons showed higher (5-7-fold) mutagenic activity when activated by the human enzyme, whereas heterocyclic amines were more mutagenic (5-75-fold) in the presence of the rat enzyme. With regard to the two aromatic amines tested, only 2-aminoanthracene showed a clear species preference, activated 3-fold more effectively by human than by rat CYP1A1. We also analyzed in silico the binding of these compounds to the human and rat enzyme catalytic sites, identifying residues expected to participate in ligand recognition. A phenylalanine residue was involved in CYP-mutagen stabilization through π-π stacking. Variations in the three-dimensional conformations and distances to the heme groups may contribute to differences between human and rat CYP-substrate interactions. In conclusion, CYP1A1 shows significant differences between species, in terms of mutagen activation, which should be considered in the context of human risk assessment.
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