2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic polychlorinated organic pollutants that have been studied. Most of the effects of TCDD are mediated by a cytosolic receptor known to as the aryl hydrocarbon receptor (AhR). Several xenobiotic-metabolizing enzymes, such as cytochrome P450 1A1 (CYP1A1), 1A2 (CYP1A2), UDP-glucuronosyltransferase, NAD(P)H-quinone oxidoreductase, and aldehyde dehydrogenase-3, have the XRE sequence, AhR-ARNT complex binding motif, in the 5'-upstream region of their genes and AhR-mediated induction of gene expression by TCDD is observed. The induction of EROD and MROD activities by TCDD were proved to be mediated by AhR, since TCDD treatment of AhR-null (Ahr-/-) mice, which lack the AhR gene, produced no enhancement of EROD and MROD activities in liver microsomes. Xanthine dehydrogenase (XDH) and xanthine oxidase(XO) activities of Ahr+/+ (C57BL/6J) mice were also increased by TCDD. However, no induction was observed in Ahr-/- mice. Thus, induction of XDH and XO activities was also mediated by AhR. XDH and XO catalyze oxidation of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of NAD+ or molecular oxygen. The reaction generates reactive oxygen species, and XO is involved in lipid peroxidation and reperfusion injury. Reactive oxygen species are generated as by-products of the action of XO/XDH. Therefore, the induction of these enzymes by TCDD may contribute significantly to the various toxicities of TCDD. In this study, we showed that XDH/XO activities are induced by TCDD and the inductions are mediated by AhR.
