Allopurinol to Febuxostat: How far have we come?

Stockert, Amy; Stechschulte, Melissa

doi:10.4137/cmt.s6286

Cited by 11 publications

(21 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In patients, allopurinol is given once per day and this is efficacious despite a relatively short half-life (~1.5h). Oxypurinol, however, has a much longer half-life (~20h), which would make it the more likely candidate responsible for XO inhibition (Stockert and Stechschulte, 2010). While the conversion of allopurinol to oxypurinol can be catalyzed by XO, it has been shown that AO is most likely the principle metabolizing enzyme and responsible for the majority of oxypurinol produced after allopurinol administration.…”

Section: Discussionmentioning

confidence: 99%

Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

Williams

McGill

Lebofsky

et al. 2014

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) has been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose.

show abstract

Section: Discussionmentioning

confidence: 99%

Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

Williams

McGill

Lebofsky

et al. 2014

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…It is a more potent inhibitor of XO than allopurinol and inhibits both XO and XOR . Additionally, febuxostat being a structurally different compound remains unaffected by HGPRT and OPRT . Topiroxostat is a recently approved XO inhibitor for the treatment of gout and hyperuricemia in Japan.…”

Section: Xanthine Oxidasementioning

confidence: 99%

“…Reported metal-based complexes(126)(127)(128)(129)(130)(131) as XO inhibitors XO inhibitor 201. Adachi et al reported in vivo study of taxifolin(125) for inhibitory activity against liver XO in liver (Fig. 22) 202.…”

mentioning

confidence: 99%

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Kumar

Joshi

Kler

et al. 2017

Medicinal Research Reviews

101

View full text Add to dashboard Cite

Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.

show abstract

“…Allopurinol, a common XO inhibitor, is most recognized for its use in the treatment of gout where its efficacy is substantial [19]. Despite the success of allopurinol, exploration for new inhibitors is necessary due to potentially severe hypersensitivity and intolerance for patients with renal failure [20]. Additionally, allopurinol has been shown to reduce the severity of oxidative damage following ischemia; however, this helps only in patients already on allopurinol therapy [18,[21][22][23][24][25][26][27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Correlation of docking energies with spectroscopic kinetic assays of potential xanthine oxidase substrates

Stockert¹,

Mahfouz²,

Petersen³

et al. 2013

JBPC

Self Cite

View full text Add to dashboard Cite

Here we present a docking model that ranks compounds according to their potential effectiveness as a potential substrate or inhibitor. We utilize xanthine oxidase (XO), a multi-cofactor oxido-reductase which converts hypoxanthine to xanthine and xanthine to uric acid. During the reductive half reaction, electrons flow from the molybdopterin, to each of two Fe/S centers, and finally to FAD. During the oxidative half reaction, electrons are passed from the FAD to O₂. Under ideal physiological conditions, this reduction of oxygen generates H₂O₂ and, under multiple turnover conditions, superoxide in amounts which is regulated by catalase and superoxide dismutase. Utilizing computer modeling predictions of the docking orientations and energies of a group of purine based structures was selected. Correlating computer estimations with steady state kinetic data, a rapid screening process for inhibittor prediction was highlighted. This method allows educated selection of likely inhibitors, thereby decreasing the time and supplies required to complete a traditional kinetic analysis screening. Results demonstrate the functionality and reliability of this method and have proven particularly useful in understanding binding orienttations or poses of each compound.

show abstract

Allopurinol to Febuxostat: How far have we come?

Cited by 11 publications

References 99 publications

Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Correlation of docking energies with spectroscopic kinetic assays of potential xanthine oxidase substrates

Contact Info

Product

Resources

About