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1 Biomedicum Helsinki, Research Program for Developmental and Reproductive Biology, Helsinki, Finland
2 Biomedicum Helsinki, Research Program for Developmental and Reproductive Biology, Helsinki, Finland; Institute of Biomedicine, University of Helsinki, Helsinki, Finland
* To whom correspondence should be addressed. E-mail: nina.linder{at}hus.fi.
Xanthine oxidoreductase (XOR) catalyzes the final reactions of purine catabolism, and may account for cell damage by producing reactive oxygen metabolites in cells reoxygenated after hypoxia. We found a 3-8-fold higher XOR activity in cultured human bronchial epithelial cells exposed to hypoxia (0.5-3% O2) compared to cells grown in normoxia (21% O2), but no difference in XOR protein or mRNA. XOR promoter constructs failed to respond to hypoxia. The cellular XOR activity at 3% O2 returned to basal levels when the cells were returned to 21% O2, and hyperoxia (95% O2) abolished enzyme activity with no change in XOR protein. Our data suggest reversible enzyme inactivation by oxygen or its metabolites. NADH was normally oxidized by the oxygen-inactivated enzyme, which rules out damage to the FAD cofactor. Hydrogen peroxide partially inactivated the molybdenum center of XOR, as shown by a parallel decrease in XOR-catalyzed xanthine oxidation and dichlorophenolindophenol reduction. We conclude that the transcription or translation of XOR are not influenced by hypoxia or hyperoxia. Instead, the molybdenum center of XOR is post-translationally inactivated by oxygen metabolites in normal (21% O2) cell culture atmosphere. This inactivation is reversed in hypoxia and accounts for the apparent induction.
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