Dehydrometabolites of siphonaxanthin, a carotenoid from green algae, suppress toll-like receptor 1/2-induced inflammatory response more strongly than siphonaxanthin

Siphonaxanthin (3, 19, 3′-trihydroxy-7, 8-dihydro-β, ε-caroten-8-one) is a carotenoid found in green algae that exhibits potent anti-inflammatory activities. We previously reported that ingested siphonaxanthin accumulates in various organs of mice; however, its metabolic conversion remains largely unknown. In this study, we isolated three siphonaxanthin dehydrometabolites and determined their chemical structures. Two of these metabolites were obtained using the postmitochondrial supernatant prepared from mouse liver, whereas the third was obtained using the postmitochondrial supernatant prepared from rat liver. The human liver S₉ fraction also generated two metabolites: one was identical to one of the rat metabolites, and the other was identical to one of the mouse metabolites. ¹H-NMR revealed that all three metabolites had one or two additional α, β-unsaturated carbonyl groups (compared with siphonaxanthin). We also evaluated their anti-inflammatory activities and found that these three metabolites suppressed toll-like receptor 1/2–mediated interferon regulatory factor (IRF) activation more potently than siphonaxanthin. Pharmacological inhibition studies revealed that activation of nuclear factor erythroid 2–related factor 2 (Nrf₂) is crucial for the inhibition of IRF activation by these metabolites. The Nrf₂-mediated decrease in the mRNA expression of the stimulator of interferon genes was determined to be one of the molecular mechanisms underlying this suppression. Thus, the hepatic metabolic conversion of siphonaxanthin generates an α, β-unsaturated carbonyl group, which boosts its IRF-inhibitory effect by activating Nrf₂.