Metabolism and Human Exposure of 2,6-dimethylaniline

2,6-Dimethylaniline (2,6-DMA) is a rat nasal cavity carcinogen and a possible human carcinogen. Human P450s 2E1 and 2A6 were identified as the major enzymes responsible for the production of its major metabolite, 4-amino-3,5-dimethylphenol (DMAP), while P450 2A6 alone was identified to be responsible for the N-hydroxylation product, N-(2,6-dimethylphenyl) hydroxylamine (DMHA) which can react with hemoglobin to form a stable adduct. P450 2E1 catalyzed intramolecular hydroxyl group rearrangement from DMHA to DMAP, and this activity of P450 2E1 was not observed with any N-hydroxy derivatives of the dimethylaniline isomers. In fact, both P450 2E1 and 2A6 contributed to the N-hydroxylation of those isomers. 2,6-DMA was oxidized to DMAP with rat P450 1A2 and 2E1, while no N- hydroxylation was observed. 2,3-, 2,5-, and 3,5-DMAs were N-hydroxylated by rat P450 1A2, and 2,4-DMA was N-hydroxylated by rat P450 2E1. Rat P450 2E1 also rearranged N-hydroxylamines of 2,3-, 2,6- and 3,5-DMAs to their corresponding para-phenols. Hemoglobin adducts of 2,6-DMA were measured in a case-control study of bladder cancer in Los Angeles County, CA. The adduct levels of 2,6-DMA were widely distributed, and bladder cancer cases have significantly increased adduct levels.