Mechanisms for the prevention of vitamin E excess

Abstract

The liver is at the nexus of the regulation of lipoprotein uptake, synthesis, and secretion, and it is the site of xenobiotic detoxification by cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III). These two major liver systems control vitamin E status. The mechanisms for the preference for α-tocopherol relative to the eight naturally occurring vitamin E forms largely depend upon the liver and include both a preferential secretion of α-tocopherol from the liver into the plasma for its transport in circulating lipoproteins for subsequent uptake by tissues, as well as the preferential hepatic metabolism of non-α-tocopherol forms. These mechanisms are the focus of this review.

Keywords: alpha-tocopherol; lipoprotein metabolism; xenobiotic metabolism.

Fig. 1.

Vitamin E structures. (A) α-Tocopherol-related structures. From top to bottom: RRR-α-tocopherol with indicated stereochemistry on the side chain and at position 2, (R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-ol; α-tocotrienol, R-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-6-ol; α-CMBHC: 2,5,7,8-tetramethyl-2(2’-carboxymethylbutyl)-6-hydroxychroman, or 5-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-2-methyl-pentanoic acid; α-CEHC: 2,5,7,8-tetramethyl-2(2’-carboxyethyl)-6-hydroxychroman, or 3-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)propanoic acid. (B) Various forms of vitamin E and its metabolites. The chromanol ring illustrated at the bottom indicates the position of the substituents at positions 5, 7, and 8 and the side-chain location. The table indicates the various substituents for each α, β, γ, and δ, as well as the side chains for tocopherols, tocotrienols, and CEHCs.

Scheme 1.

Relationship between vitamin E in diet, circulation, liver, and excretion. The α-tocopherol and α-CEHC are shown in a rose color, with higher concentrations indicated by darker colors. For all panels, as the vitamin E intake moves from low (<5 mg/day), to adequate (10–50 mg/day), to very high (>1,000 mg/day), the intensity of the color increases. Components with no color change (e.g., α-TTP) do not vary with vitamin E intake. Note that OATP varies inversely with vitamin E intake.