Potential of Vitamin E Deficiency, Induced by Inhibition of α-Tocopherol Efflux, in Murine Malaria Infection

Abstract

Although epidemiological and experimental studies have suggested beneficial effects of vitamin E deficiency on malaria infection, it has not been clinically applicable for the treatment of malaria owing to the significant content of vitamin E in our daily food. However, since α-tocopherol transfer protein (α-TTP) has been shown to be a determinant of vitamin E level in circulation, manipulation of α-tocopherol levels by α-TTP inhibition was considered as a potential therapeutic strategy for malaria. Knockout studies in mice indicated that inhibition of α-TTP confers resistance against malaria infections in murines, accompanied by oxidative stress-induced DNA damage in the parasite, arising from vitamin E deficiency. Combination therapy with chloroquine and α-TTP inhibition significantly improved the survival rates in murines with malaria. Thus, clinical application of α-tocopherol deficiency could be possible, provided that α-tocopherol concentration in circulation is reduced. Probucol, a recently found drug, induced α-tocopherol deficiency in circulation and was effective against murine malaria. Currently, treatment of malaria relies on the artemisinin-based combination therapy (ACT); however, when mice infected with malarial parasites were treated with probucol and dihydroartemisinin, the beneficial effect of ACT was pronounced. Protective effects of vitamin E deficiency might be extended to manage other parasites in future.

Keywords: Vitamin E; artemisinin-based combination therapy (ACT); chloroquine; oxidative stress; probucol; α-tocopherol; α-tocopherol transfer protein (α-TTP).

Figure 1

Possible induction of vitamin E deficiency by the inhibition of α-tocopherol efflux from liver cells. Both α- and γ-tocopherols are absorbed similarly from the intestine and transported by chylomicrons in plasma. Following the uptake of chylomicrons by the liver, only α-tocopherol is preferentially transported and localized to plasma membrane of liver cells by α-tocopherol transfer protein (α-TTP). It is subsequently incorporated into lipoproteins, resulting in recirculation of this tocopherol in the body. On the other hand, γ-tocopherol is taken up by the liver and eventually secreted into bile. ATP-binding cassette transporter A1 (ABCA1) participates directly in the transport of α-tocopherol from liver cells to Apo A-I, which is the major protein component of HDL. Thus, α-TTP or ABCA1 might be suitable targets to induce vitamin E deficiency in circulation.