Fucoxanthin Enhances HO-1 and NQO1 Expression in Murine Hepatic BNL CL.2 Cells through Activation of the Nrf2/ARE System Partially by Its Pro-oxidant Activity

To determine whether fucoxanthin, a major carotenoid in brown sea algae, may activate cellular antioxidant enzymes via up-regulation of the Nrf2/antioxidant-response element (ARE) pathway, we incubated mouse hepatic BNL CL.2 cells with fucoxanthin (0.5-20 mu M) for 0-24 h. We found that fucoxanthin (>= 5 mu M) significantly increased cellular reactive oxygen species (ROS) at 6 h of incubation, whereas preincubation with alpha-d-tocopherol (30 mu M) significantly attenuated the increase of ROS, indicating the pro-oxidant nature of fucoxanthin. Fucoxanthin significantly increased the phosphorylation of ERK and p38 and markedly increased nuclear Nrf2 protein accumulation after incubation for 12 h. Moreover, fucoxanthin significantly enhanced binding activities of nuclear Nrf2 with ARE and increased mRNA and protein expression of HO-1 and NQO1 after incubation for 12 h. siRNA inhibition of Nrf2 led to markedly decreased HO-1 and NQO1 protein expression. Thus, fucoxanthin may exert its antioxidant activity, at least partly, through its pro-oxidant actions.