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While much has been learned about xanthine oxidoreductase, much remains to be uncovered. Understanding its exact role in lipid peroxidation, inflammation, and infection is particularly important. Its significance to drug metabolism remains to be determined.

5.05.2.5 Aldehyde Oxidase (AOX)

AOX is closely related to xanthine oxidoreductase, and like xanthine oxidoreductase is a member of the structurally related molybdoflavoenzymes. AOX and xanthine oxidoreductase have overlapping substrate selectivities, and operate by the same chemical mechanism.196 As the name implies, one of the primary reactions that AOX catalyzes is the oxidation of aldehydes to carboxylic acids. For example, it contributes to the oxidation of acetaldehyde resulting from alcohol ingestion. Unfortunately, it also seems to be implicated in alcohol-induced liver injury because of the free radicals it generates in the process of oxidizing acetaldehyde.197

In oxidizing aldehydes, AOX appears to operate by the same mechanism it utilizes to oxidize purines. This is illustrated for the conversion of 2,5-dihydroxyacetaldehyde (170) to 2,5-dihydroxybenzoic acid193 (171) (Figure 8).

AOX is also effective in metabolizing a wide range of nitrogen-containing heterocycles, such as purines, pyrimid-ines, pteridines, quinolines, and diazanaphthalenes.198,199 For example, phthalazine (172) is rapidly converted to 1-phthalazinone (173) (eqn [50]),200 the prodrug 5-ethynyl-2-(1H)-pyrimidone (174) is oxidized to the dihydro-pyrimidine dehydrogenase mechanism-based inhibitor 5-ethynyluracil (175) (eqn [51]),201 and the prodrug famciclovir (176) is first hydrolyzed to 6-desoxypanciclovir (177), before being oxidized to the active antiviral agent panciclovir (178) by AOX (Scheme 18).202

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