Physiological Role of Ascorbic Acid in Xenobiotic Metabolism and Protection Against Oxidative Stress

Abstract

We examined physiological roles of ascorbic acid (AsA) using the ODS-od/od (ODS) rat with a hereditary defect in AsA biosynthesis. AsA deficiency decreased both the hepatic content of cytochrome P-450 (CYP) and the hepatic activities of xenobiotic-metabolizing enzymes in ODS rats treated and not treated with xenobiotics such as polychlorinated biphenyls (PCBs). In ODS rats feeding a PCB-containing diet, the hepatic mRNA level of phenobarbital-inducible CYP2B1/2B2 in AsA-deficient rats was lower than that in rats fed sufficient AsA. Moreover, the requirement of AsA was increased by the administration of PCBs for the maximal induction of xenobiotic-metabolizing enzyme activities. The role of AsA as a physiological antioxidant was examined in ODS rats injected with lipopolysaccharide (LPS), which is recognized to produce oxidative stress. Feeding AsA suppressed the increase of bilirubin oxidative metabolites in urine caused by the LPS treatment. Feeding AsA also suppressed the induction of hepatic heme oxygenase-1, whose expression is stimulated by oxidative stress caused by the LPS treatment. These results indicate that AsA acts as a physiological antioxidant in oxidative stress synergistically with bilirubin.