A Metabolomic Investigation of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) Metabolism in the Mouse

TL;DRAbstract

PhIP is a potent rodent carcinogen and a potential human carcinogen because of its existence in the normal human diet. Several major PhIP metabolites were identified, including N2‐OH‐PhIP, 4′‐OH‐PhIP, 5‐OH‐PhIP and their corresponding glucuronide and sulfate conjugates. Among these, N2‐OH‐PhIP is the precursor metabolite that can further be transformed into a genotoxic species by O‐acetylation or O‐sulfation. In vitro data support the view that CYP1A2 is the major enzyme responsible for formation of N2‐OH‐PhIP. However, disruption of the mouse Cyp1a2 gene failed to inhibit the PhIP‐induced carcinogenesis. To investigate the mechanism underlying this observation, the metabolism of PhIP in wild‐type, Cyp1a2‐null and CYP1A2‐humanized mice was examined using LC‐MS‐based metabolomics, and the relative abundance of major PhIP metabolites was further quantified by a radio‐HPLC assay. Furthermore, genotoxicity of PhIP in three mouse lines was evaluated by measuring DNA adduct levels in liver,

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