Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells.

1. Chrysin is one of many bioflavonoids with chemopreventive properties in cardiovascular disease and cancer. In an effort better to understand factors that may affect the oral bioavailability of the bioflavonoids from dietary sources, the metabolism of chrysin by cultured intestinal Caco-2 cells and hepatic Hep G2 cells was studied, together modelling human presystemic metabolism. 2. At concentrations that may be achieved in the diet, chrysin was extensively metabolized to two conjugated metabolites, M1 and M2, with no CYP-mediated oxidation. M1 was identified as a glucuronide, and M2 as a sulphate conjugate by LC/MS and other spectroscopic and biochemical techniques. Sulphate conjugation occurred at a rate twice that of glucuronic acid conjugation in both cell types. 3. M1 was catalyzed by UGT1A6 with a Km = 12 microM. M2 was catalyzed both by M- and P-form phenolsulphotransferases (SULT 1A3 and SULT 1A1) with very low Km of 3.1 and 0.05 microM respectively. 4. Pretreatment with 3-methylcholanthrene, interestingly, did not result in oxidation of chrysin but rather in increased glucuronidation. 5. Also, M1 and M2 were the only metabolites formed from chrysin in fresh rat hepatocytes. The metabolism of another flavonoid, apigenin, was very similar to that of chrysin. 6. These observations suggest that both sulphation and glucuronidation are critical determinants of the oral bioavailability of bioflavonoids in humans, although a contribution from CYP-mediated oxidation can not be excluded.