Modulation of inflammatory signaling by vitamin E metabolites and its therapeutic implications

Naturally occurring vitamin E is a lipophilic plant-derived molecule corresponding to the 2 R forms of alpha-tocopherol. A series of natural analogs or tocochromanols are present in nature, including β-, γ- and δ-tocopherol (βT, γT, δT), the corresponding tocotrienols (αTE, βTE, γTE, δTE) and tocomonoenols. Differences between these analogs as lipophilic antioxidants and modulators of molecular processes suggest specific therapeutic properties against various disorders associated with acute and chronic inflammation. However, hepatic metabolism of these compounds via cytochrome P450-initiated side chain ω-oxidation involves the production of long-chain metabolites (LCMs) followed by intermediate (ICMs) and short-chain metabolites (SCMs), respectively. Despite the initial studies indicating these metabolites as catabolic-end products, recent findings identify their importance in providing biological functions. In this scope, LCMs, especially 13'-carboxychromanols (13'-COOHs), have been reported to hold stronger anti-inflammatory capacity than their unmetabolized precursors due to their ability to inhibit 5-lipoxygenase and cyclooxygenase-catalyzed eicosanoid formation, as well as their modulation of the pro-inflammatory transcriptional protein nuclear factor κB (NF-κB). Also, these LCMs have been reported to enhance detoxification and lipid metabolism pathways associated with cellular inflammation by modulating the nuclear receptors peroxisome proliferator-activated receptor-γ (PPARγ) and pregnane x receptor (PXR). These properties of LCMs will be described in this narrative review article focusing on recent information regarding their bioavailability, anti-inflammatory effects, and mechanisms of action in acute and chronic inflammatory disorders.