Vitamin E status and metabolism in adult and aged aryl hydrocarbon receptor null mice

Abstract

The aryl hydrocarbon receptor (AhR) is involved in regulation of mechanisms for detoxification of xenobiotics, as well as vitamin A metabolism. Vitamin E is a fat-soluble nutrient whose metabolism is initialized via the cytochrome P450 system. Thus, AhR absence could alter hepatic regulation of α-tocopherol metabolism. To test this hypothesis, we assessed vitamin E status in adult (2-5 m) and old (21-22 m), wild-type and AhR-null mice. Plasma α-tocopherol concentrations in AhR-null mice (2.3±1.2 μmol/L, n=19) were lower than those of wild-type mice (3.2±1.2, n=17, P=.0131); those in old mice (3.2±1.2, n=20) were higher than those of adults (2.2±1.0, n=16, P=.0075). Hepatic α-tocopherol concentrations were not different between genotypes, but were nearly double in old (32±8 nmol/g, n=20) as compared with adult mice (17±2, n=16, P<.0001). Hepatic Cyp3a concentrations in AhR-null mice were greater than those in wild-type mice (P=.0011). Genotype (P=.0047), sex (P<.0001) and age (P<.0001) were significant modifiers of liver α-tocopherol metabolite (α-CEHC) concentrations. In general, Cyp3a concentrations correlated with hepatic α-tocopherol (r=0.3957, P<.05) and α-CEHC (r=0.4260, P<.05) concentrations. Since there were no significant genotype differences in the hepatic α- or γ-tocopherol concentrations, AhR-null mice did not have dramatically altered vitamin E metabolism. Since they did have higher hepatic α-CEHC concentrations, these data suggest metabolism was up-regulated in the AhR-null mice in order to maintain the hepatic tocopherol concentrations similar to those of wild-type mice.

Figure 1. Plasma Vitamin E and Triglyceride Concentrations

Plasma α-tocopherol (μmol/L, A), triglyceride (mmol/L, B) and α-tocopherol per triglycerides (mmol/mol, C) are shown for adult (solid bars) and old (striped bars) from AhR null and wildtype mice. Plasma α-tocopherol concentrations were higher in Ahr null compared with wildtype mice (p<0.01, genotype effect) and higher in young than in old mice (p<0.01, age effect). Plasma triglycerides were higher in old wildtypes (a) than any other group (b; age × genotype, P=0.0389, Tukey HSD, p<0.05). Plasma α-tocopherol per triglycerides were nearly double in old AhR mice compared with their adult counterparts (age × geneotype, p=0.019; Tukey, HSD, p<0.05). In each graph, bars not bearing the same letter are significantly different.

Figure 2. Hepatic Cyp3a and Cyp4f Concentrations

Hepatic Cyp3a concentrations in AhR null (arbitrary units relative to actin, n=15) and wildtype (n=15) mice, in female (striped bars, n=13) and male mice (solid bars, n=17) are shown in A; representative western blots from individual animals are shown in B. Hepatic Cyp4f concentrations in female (arbitrary units relative to actin, n=14) and male mice (n=17) are shown in C; representative western blots from individual animals are shown in D.