Potent 3-methylindole-mediated DNA damage, cytochrome P450 induction, and mutagenicity in human lung

3-methylindole (3MI) is a preferential pneumotoxicant known to be present in cigarette smoke at concentrations previously demonstrated to cause pulmonary damage in experimental animals. Human cytochrome P450 (CYP450) enzymes, including 1A1, 2A13, and 2F1 catalyze the dehydrogenation of 3MI to the reactive intermediate 3-methyleneindolenine (3MEIN). This metabolite alkylates DNA. Alkyl DNA adducts have previously been demonstrated to play a role in the induction of xenobiotic-mediated apoptosis, mutagenesis, and carcinogenesis. In addition, 3MI induces the expression of cytochrome P450 enzymes in experimental animals. owever, the ability of 3MI to induce these effects in human lung has not been elucidated to date. The hypothesis for this work is that cytochrome P450-mediated metabolism of 3MI causes DNA damage, cytochrome P450 induction, and mutagenesis in human lung.