**2.4. Hepatic metabolism of vitamin E**

The hepatic metabolism of vitamin E has not been fully characterized. However, the principle steps of vitamin E degradation, that is, the shortening of the side chain without the alteration of the chroman ring, are generally accepted. Hence, the metabolites are classified as α-, β-, γ-, and δ-metabolites according to their respective precursors.

In principle, TOHs and T3s are degraded like long branched chain fatty acids (TOH) or long unsaturated branched chain fatty acids (T3) via β-oxidation in peroxisomes. However, as TOHs and T3s do not bear a terminal carboxy function in their side chain, they are not susceptible to β-oxidation. Hence, the initial and rate-limiting step in vitamin E degradation is the introduction of a carboxy function to the ω-terminus of the side chain. This first step is carried out in the endoplasmic reticulum (ER) of liver cells [44]. Here, two representatives of the cytochrome P450 (CYP) protein family, namely, CYP4F2 [45] and CYP3A4 [46, 47], have been identified to catalyze the initial ω-hydroxylation step. The resulting 13′-hydroxychromanol (13′-OH) is then further metabolized via ω-oxidation, a step that most likely involves alcohol dehydrogenase and aldehyde dehydrogenase [44], leading to 13′-carboxychromanol (13′-COOH). The carboxylated side chain resembles a long branched chain fatty acid that is further degradable via β-oxidation. However, a transport mechanism for the carboxychromanol from the ER to the peroxisomes has not been identified so far. Nevertheless, two cycles of peroxisomal β-oxidation after the activation of α-13′-COOH to the respective CoA ester have been suggested [44], as the peroxisomal β-oxidation system has a higher affinity toward long branched chain fatty acids than the mitochondrial counterpart [48]. The proposed 11′- and 9′-COOH metabolites have indeed been identified in human and mouse samples [49] as well as in a hepatic cell line [45, 50]. Subsequently, three more cycles of β-oxidation are needed to form the final product of vitamin E degradation, namely, carboxyethyl hydroxychromanol (CEHC) or 3′-COOH. These steps, however, are assigned to mitochondrial β-oxidation, as CEHC has solely been found in the mitochondria of hepatic cells [44]. Again, the transport mechanisms of the long-chain metabolites (LCM) (13′- to 9′-COOHs) from peroxisomes to the mitochondria are not known. The respective products for each cycle of β-oxidation (7′-COOH, 5′-COOH, and 3′-COOH) have been identified in different human and murine tissues [49, 51–54] as well as the hepatic cell line HepG2 [45, 47, 51]. Taken together, the hepatic metabolism of vitamin E is characterized by a series of β-oxidation steps after an initial introduction of a carboxy moiety at the ω-terminus of the phytyl-like side chain. The metabolism likely takes place in different cell compartments depending on the enzymatic systems needed for the different degradation steps. However, a concept of vitamin E degradation exclusively in mitochondria cannot be excluded [44]. T3 degradation is believed to follow the same route as TOH degradation but requiring further steps due to the unsaturated side chain. In line with this assumption is the identification of the respective unsaturated metabolites from 13′-carboxytrienol down to carboxymethylbutadienylhydroxychromanol (CMBenHC) in human and mouse samples [49]. According to these findings, the side chain of the T3 metabolites needs a saturation step before the shortening of the chain. Enzymes involved in the degradation of unsaturated fatty acids like 2,4-dienoyl-CoA reductase and 3,2-enoyl-CoA isomerase were suggested to contribute to the degradation of T3s [55].
