Xanthine Oxidoreductase in Drug Metabolism: Beyond a Role as a Detoxifying Enzyme

Abstract

The enzyme xanthine oxidoreductase (XOR) catalyzes the last two steps of purine catabolism in the highest uricotelic primates. XOR is an enzyme with dehydrogenase activity that, in mammals, may be converted into oxidase activity under a variety of pathophysiologic conditions. XOR activity is highly regulated at the transcriptional and post-translational levels and may generate reactive oxygen and nitrogen species, which trigger different consequences, ranging from cytotoxicity to inflammation. The low specificity for substrates allows XOR to metabolize a number of endogenous metabolites and a variety of exogenous compounds, including drugs. The present review focuses on the role of XOR as a drug-metabolizing enzyme, specifically for drugs with anticancer, antimicrobial, antiviral, immunosuppressive or vasodilator activities, as well as drugs acting on metabolism or inducing XOR expression. XOR has an activating role that is essential to the pharmacological action of quinone drugs, cyadox, antiviral nucleoside analogues, allopurinol, nitrate and nitrite. XOR activity has a degradation function toward thiopurine nucleotides, pyrazinoic acid, methylxanthines and tolbutamide, whose half-life may be prolonged by the use of XOR inhibitors. In conclusion, to avoid potential drug interaction risks, such as a toxic excess of drug bioavailability or a loss of drug efficacy, caution is suggested in the use of XOR inhibitors, as in the case of hyperuricemic patients affected by gout or tumor lysis syndrome, when it is necessary to simultaneously administer therapeutic substances that are activated or degraded by the drug-metabolizing activity of XOR.

Fig. (1)

Purine catabolism and the purine salvage pathway. AMP, GMP, IMP and XMP are the monophosphate nucleotides of adenine, guanine, hypoxanthine and xanthine, respectively. The purine salvage pathways are indicated with red arrows, and the green arrows refer to the reactions catalyzed by XOR activity (reviewed in [1]).

Fig. (2)

Molecular structure and catalytic electron flow of xanthine oxidoreductase (XOR). Each XOR monomer consists of (I) a C-terminal domain of approximately 85 kDa (blue) that includes a molybdenum-containing molybdopterin cofactor (Moco) and a binding site for purine and nitrate/nitrite substrates; (II) an intermediate domain of approximately 40 kDa (yellow) that contains the flavin adenine dinucleotide (FAD) cofactor, which delivers the electrons to the final acceptor, either oxidized nicotinamide adenine dinucleotide or molecular oxygen, generating reactive molecular species; and (III) an N-terminal domain of approximately 20 kDa (red) that contains the iron-sulfur clusters Fe/S I and Fe/S II, which convey the electrons from Moco to FAD (reviewed in [3-5]).

Fig. (3)

Antiblastic drugs. Structural formulas of the quinone antibiotics doxorubicin, menadione, mitomycin C and streptonigrin and the purine analogues 6-mercaptopurine and 6-thioguanine. The positions of catalytic oxidation by xanthine oxidoreductase are indicated by arrows.

Fig. (4)

Bactericidal drugs. Structural formulas of the quinoxaline-1,4-di-N-oxide cyadox and of the anti-tuberculosis agent pyrazinoic acid. The position of catalytic oxidation by xanthine oxidoreductase is indicated by arrow.

Fig. (5)

Antiviral drugs. Structural formulas of purine nucleoside analogues, which are prodrugs of antiviral compounds. The positions of catalytic oxidation by xanthine oxidoreductase are indicated by arrows.

Fig. (6)

Metabolic drugs. Structural formulas of 1-methylxanthine, tolbutamide and allopurinol. The arrows indicate the position of xanthine oxidoreductase catalysis.