γ-Tocotrienol Ameliorates Intestinal Radiation Injury and Reduces Vascular Oxidative Stress after Total-Body Irradiation by an HMG-CoA Reductase-Dependent Mechanism

Abstract

Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of injury to the hematopoietic, intestinal and vascular/ endothelial systems were assessed after exposure to total-body irradiation. GT3 improved postirradiation survival and decreased radiation-induced vascular oxidative stress, an effect that was reversible by mevalonate. GT3 also enhanced hematopoietic recovery, reduced intestinal radiation injury, and accelerated the recovery of soluble markers of endothelial function. These parameters were not reversed by mevalonate co-administration. Our data confirm GT3's radioprophylactic properties against hematopoietic injury and, for the first time, demonstrate benefits in terms of protection against gastrointestinal and vascular injury. The radioprotective efficacy of GT3 against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.

Metabolism of tocotrienols in animals and synergistic inhibitory actions of tocotrienols with atorvastatin in cancer cells

“…Similarly, only triglyceride levels were reduced in carbon tetrachloride-induced fatty liver in rats (Yachi et al 2010). In addition to cholesterol-related metabolism, Berbee et al (2009) showed that c-T3 improved post-irradiation survival and decreased radiation-induced vascular oxidative stress after a total-body irradiation. The effect of c-T3 could be eliminated by mevalonate, the product of the reaction catalyzed by HMGCR, suggesting that the protective role of c-T3 was through an HMGCR-dependent mechanism.…”

Mechanisms underlying the radioprotective properties of γ-tocotrienol: comparative gene expression profiling in tocol-treated endothelial cells

“…Because of relatively potent antioxidant properties and lack of performance-degrading side effects, vitamin E analogs, collectively referred to as tocols, are considered to be attractive candidate agents for radioprotection. In recent years, various tocols have been tested for their radioprotective potential (Berbee et al 2009;Kumar et al 2002;Singh et al 2006). Important structural and functional differences exist between the different tocols.…”

“…In a direct side-by-side comparison, Kumar et al demonstrated that GT3 is superior to a-tocopherol in reducing lethality after total body irradiation (TBI) in mice (Kumar et al 2008). Subsequent studies have shown that the radioprotective properties of GT3 not only depend on its antioxidant action but also on the modulation of endothelial cell function (Berbee et al 2009). Endothelial dysfunction is a prominent feature of early as well as late radiation injury and has been shown to play an important role in the pathogenesis of radiation toxicity in various organ systems (Baker and Krochak 1989;Hopewell et al 1993;Jaenke et al 1993;Lyubimova and Hopewell 2004;Maj et al 2003;Paris et al 2001;Rezvani et al 1995;Wang et al 2002Wang et al , 2007.…”

“…GT3, in contrast to a-tocopherol, is a potent inhibitor of endothelial 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (Parker et al 1993;Song and DeBose-Boyd 2006). Moreover, after radiation exposure of mice in vivo, GT3 reduces radiation-induced vascular oxidative stress in an HMG-CoA reductase dependent manner (Berbee et al 2009). GT3 may also exert its beneficial inhibitory effects on postirradiation free-radical production by improving the availability of the endothelial nitric oxide synthase (eNOS) cofactor BH4 through downregulation of GTP-cyclohydrolase 1 regulatory protein (GFRP), thereby enhancing the production of NO and reducing the production of ONOO-by eNOS (Berbee et al 2011).…”

“…GT3 may also exert its beneficial inhibitory effects on postirradiation free-radical production by improving the availability of the endothelial nitric oxide synthase (eNOS) cofactor BH4 through downregulation of GTP-cyclohydrolase 1 regulatory protein (GFRP), thereby enhancing the production of NO and reducing the production of ONOO-by eNOS (Berbee et al 2011). Finally, GT3 has been shown to improve the postirradiation recovery of plasma markers of endothelial function, an effect that is not dependent of HMG-CoA reductase inhibition (Berbee et al 2009). …”