Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver

Curcumin and its natural congeners are of current interest because of their putative anti-inflammatory and anticarcinogenic activities, but knowledge about their metabolic fate is scant. In the present study conducted with precision-cut liver slices from male and female Sprague-Dawley rats, five reductive but no oxidative metabolites of curcumin and its demethoxy and bis-demethoxy analogues were observed and identified by HPLC and GC-MS analysis, mostly by comparison with authentic reference compounds. The major reductive metabolites were the hexahydrocurcuminoids in both male and female rat liver slices, whereas male rats formed more octahydro than tetrahydro metabolites and female rats more tetrahydro- than octahydrocurcuminoids. Tetrahydro, hexahydro, and octahydro metabolites were predominantly present as glucuronides, but a significant proportion of sulfate conjugates was also observed. The lack of formation of oxidative metabolites of curcumin and the ready generation of reductive metabolites were confirmed using rat liver microsomes and cytosol, respectively. Results of enzymatic hydrolysis studies conducted under various conditions revealed that curcumin and demethoxycurcumin are chemically less stable than bis-demethoxycurcumin, whereas the reductive metabolites of all three curcuminoids are stable compounds. This is the first report on the metabolism of demethoxycurcumin and bis-demethoxycurcumin. In view of the chemical instability of the parent curcuminoids, it is proposed to use their major phase I metabolites, that is, the stable hexahydro products, as biomarkers for exposure in clinical studies.