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CELLULAR METABOLISM

Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions

Hospital for Children and Adolescents, Research Program for Developmental and Reproductive Biology, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland

Submitted 2 December 2002 ; accepted in final form 28 February 2003

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 three- to eightfold higher XOR activity in cultured human bronchial epithelial cells exposed to hypoxia (0.5–3% O₂) compared with 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 flavin adenine dinucleotide 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 is not influenced by hypoxia or hyperoxia. Instead, the molybdenum center of XOR is posttranslationally inactivated by oxygen metabolites in "normal" (21% O₂) cell culture atmosphere. This inactivation is reversed in hypoxia and accounts for the apparent induction.

xanthine oxidase; hypoxia; hyperoxia; ischemia reperfusion

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