Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes

A series of naturally occurring as well as synthetic structural analogs of the dietary constituent curcumin were examined in order to elucidate which portions of the molecule are critical for the ability to induce Phase 2 det oxification enzymes in murine hepatoma cells, and hence to assess the chemo protective potential of these compounds, Two groups of compounds were studi ed: classical Michael reaction accepters such as curcumin and related beta- diketones such as dibenzoylmethane which lack direct Michael reactivity. Th e presence of two structural elements was found to be required for high ind ucer potency: (i) hydroxyl groups at ortho-position on the aromatic rings a nd (ii) the beta-diketone functionality. All curcuminoids elevate the speci fic activity of quinone reductase in both wild type and mutant cells defect ive in either the aryl hydrocarbon (Ah) receptor or cytochrome P4501A1 acti vity. This indicates that neither binding to this receptor, nor metabolic a ctivation by P4501A1 are required for the signaling process originating fro m this family of electrophiles and ultimately resulting in Phase 2 enzyme i nduction.