α‐tocopherol affects the urinary and biliary excretion of 2,7,8‐trimethyl‐2(2′‐carboxyethyl)‐6‐hydroxychroman, γ‐tocopherol metabolite, in rats

Abstract

In this study, we investigated a change in the excretory content of 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC), a gamma-tocopherol (gamma-Toc) metabolite, in rat urine and bile by using a new high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. In this determination, CEHC [alpha- and gamma-CEHC, where alpha-CEHC = 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman] in the biological specimens were treated with 3 N methanolic HCl to hydrolyze conjugates and to promote esterification. The methylated samples were extracted by n-hexane/water (1:2). The analyses of the methyl esters of alpha-CEHC and gamma-CEHC were performed by an HPLC-ECD using an ODS-3 column at 35 degrees C. The mobile phase was acetonitrile/water (45:55, vol/vol) containing 50 mM sodium perchlorate. After rat urine and bile samples, respectively, were methylated as described above, methylated biliary metabolites were identified by liquid chromatography-mass spectrometry as methyl esters of gamma-CEHC. Furthermore, we examined the differences in the excretion of gamma-CEHC between rat urine and bile after an oral administration of gamma-Toc or alpha- + gamma-Toc by the above HPLC method. In the gamma-Toc group, each vitamin E-deficient rat was given 0.5 mL of a stripped corn oil preparation containing 10 mg of gamma-Toc. In the alpha- + gamma-Toc group, the rat was given 10 mg of alpha-Toc and 10 mg of gamma-Toc. The content of gamma-CEHC in rat urine from the alpha- + gamma-Toc group was increased more in comparison to the gamma-Toc group at 18-36 h after oral administration. Moreover, the content of gamma-CEHC in rat bile in the alpha- + gamma-Toc group was increased more in comparison to the gamma-Toc group at 6-18 h after oral administration. Therefore, we have suggested that gamma-CEHC was shifted mainly to urinary excretion after gamma-CEHC had been excreted into the bile. Furthermore, we assume that alpha-Toc may affect the metabolism of gamma-Toc to gamma-CEHC in the body.

The effect of γ-tocopherol administration on α-tocopherol levels and metabolism in humans

“…Tocopherol metabolism, especially that of g-tocopherol or gtocotrienol, and the effects of tocopherols on sodium secretion in rats have been examined by various authors (Clement & Bourre, 1997;Hattori et al, 2000a;Kiyose et al, 2001;Ikeda et al, 2002;Saito et al, 2003). Kiyose et al (2001) investigated the differences of g-CEHC excretion in urine and bile after the oral administration of g-tocopherol or a-þ g-tocopherol to rats, and concluded that a-tocopherol may influence the in vivo metabolism of g-tocopherol to g-CEHC.…”

“…Kiyose et al (2001) investigated the differences of g-CEHC excretion in urine and bile after the oral administration of g-tocopherol or a-þ g-tocopherol to rats, and concluded that a-tocopherol may influence the in vivo metabolism of g-tocopherol to g-CEHC.…”

“…The decrease in g-tocopherol after a-tocopherol supplementation is considered to be due to the acceleration of g-tocopherol metabolism (Morinobu et al, 2003). Kiyose detected the excretion of g-CEHC in vitamin E-deficient rats receiving a-and g-tocopherol supplementation, and suggested that a-tocopherol might influence the transformation of g-tocopherol to g-CEHC (Kiyose et al, 2001). Regarding the vitamin E metabolism after g-tocopherol administration, Clement studied rats fed a diet with a constant content of RRR-atocopherol plus various amounts of RRR-g-tocopherol, and found that the tissue levels of a-tocopherol were much higher than those in rats fed a control diet containing RRR-atocopherol alone (Clement & Bourre, 1997).…”

Measurement of vitamin E metabolites by high-performance liquid chromatography during high-dose administration of α-tocopherol

“…Stahl investigated the plasma levels of a-CEHC and 2,7,8-trimethyl-2(2 0 -carboxyethyl)-6-hydroxychroman (g-CEHC) in healthy adults taking a-tocopherol, and reported that there was only a slight elevation of g-CEHC (Stahl et al, 1999). Kiyose demonstrated the excretion of g-CEHC after a-and g-tocopherol supplementation in vitamin E deficient rats, and suggested a-tocopherol might affect the metabolism of gtocopherol to g-CEHC (Kiyose et al, 2001). It is also known that tocotrienols, other members of the vitamin E family, are metabolized to CEHCs as well as tocopherols and then excreted in the urine (Lodge et al, 2001).…”

Adverse effects of vitamin E by induction of drug metabolism

“…However, the metabolism of vitamin E is indeed very similar in humans and animals. In both, the mechanism of side chain degradation is identical, as is the low degradation rate of a-tocopherol when compared to other forms of vitamin E (reviewed in [15]); all rac-atocopherol is degraded faster than RRR-a-tocopherol [35,74]; c-tocopherol levels are similarly decreased by high dosages of a-tocopherol [36,57] and c-tocopherol metabolism is equally impaired in humans and rats by inhibition of CYP3A [48,31]. In view of these observations, the possibility that a-tocopherol also induces enzymes involved in drug metabolism in humans can not be disregarded, but needs to be investigated, because the system displays species specificity, with particular in respect to the response to inducers.…”