Hepatic processing determines dual activity of α-tocopheryl succinate: a novel paradigm for a shift in biological activity due to pro-vitamin-to-vitamin conversion

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Abstract

Redox-silent vitamin E analogues, represented by α-tocopheryl succinate, are potent anti-cancer drugs with potential secondary bioactivity due to their processing in vivo. Here we verified the hypothesis that hepatic processing of these agents determines the secondary effect. Mice were repeatedly injected with α-tocopheryl succinate, and their systemic and hepatic vein blood was assessed for α-tocopheryl succinate and its hydrolysis product, vitamin E (α-tocopherol). While levels of α-tocopherol doubled compared to control mice and α-tocopheryl succinate accumulated in the systemic blood, no α-tocopheryl succinate was detected in blood draining the liver. We conclude that hepatic processing endows compounds like α-tocopheryl succinate with a secondary, anti-oxidant/anti-inflammatory activity due to converting it to the redox-active α-tocopherol. Our finding epitomises a novel, general paradigm, according to which a drug can be converted in the liver into a product that has a different beneficial bioactivity.

Section snippets

Materials and methods

C57BL mice were used at 7–9 weeks of age. The animals (5 per group) were injected every third day with 100 μl of 100 mM α-TOS (RRR-α-TOS; Sigma) in DMSO or with 100 μl DMSO alone (control mice). Twenty-four hours following the last injection, hepatic and systemic blood was collected under a stereomicroscope as follows. A heparinised 1-ml syringe (26 g needle) was carefully inserted into the hepatic vein draining the left lobe in an anaesthetised mouse and ∼200 μl of hepatic blood was withdrawn

Results and discussion

Previous circumstantial data suggested that α-TOS may be cleaved in vivo, presumably in the liver, whereby it is converted into the redox-active α-TOH. This is largely based on studies in which higher (2- to 3-fold) levels of α-TOH were observed in the circulation of mice subjected to chronic intraperitoneal administration of α-TOS at doses, at which the pro-vitamin strongly suppressed tumour growth in pre-clinical models [3], [5]. Thus, it was apparent that disposition of α-TOS in vivo

Acknowledgment

This work was supported by grants from the Queensland Cancer Fund and the Australian Research Council to J.N.

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      Considering this as an alternative explanation we next asked whether the antioxidant activity of α-tocopherol was necessary to exert its protective effect. In fact, the effect reported with the redox-silent analogue α-TOS could support this idea, although caution is required when interpreting those results because this compound could be hydrolyzed in vivo yielding active α-tocopherol (25, 26). Actually, the delay observed in the protective effect of α-TOS when compared with that of α-tocopherol (Fig. 3E) could be explained if processing α-TOS to the active vitamin form is a prerequisite.

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    Abbreviations: NSE, non-specific esterase; α-TOH, α-tocopherol; α-TOS, α-tocopheryl succinate; α-TTP, α-tocopheryl transfer protein; VLDL, very low-density lipoprotein.

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