Aldehyde Oxidase Activity and Inhibition in Hepatocytes and Cytosolic Fraction from Mouse, Rat,Monkey and Human

Sahi, Jasminder; Khan, Kishore K.; Black, Chris

doi:10.2174/187231208785425818

Cited by 62 publications

(42 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the fact that our overall results were in agreement with species difference of AO catalytic activity reported in the literature (Kitamura et al, 2006;Sahi et al, 2008;Pryde et al, 2010), more robust AO activity oxidizing 5BPO and related oxazoles was observed in mouse liver cytosol over monkey or human liver cytosol. This could possibly be an oxazole-chemotype-specific or compound-specific phenomenon.…”

Section: Downloaded Fromsupporting

confidence: 90%

“…Likewise, metabolite resulting from oxidation of zoniporide by AO in the quinoline ring was a primary metabolite in humans and rats but was not observed in dogs . On the other hand, zebularine was found to be metabolized by AO with higher V max observed in mouse than in human and monkey liver cytosols (Klecker et al, 2006), and the order of AO activity, measured by the rate of vanillic acid formation from vanillin, was monkey Ͼ mouse Ͼ human Ͼ rat liver cytosol, with no activity seen in dog cytosol (Sahi et al, 2008). When 5BPO was incubated in liver cytosols from various species including the rat, mouse, dog, monkey, and human (Table 3), maximal turnover of 5BPO was observed in mouse liver cytosol (t 1/2 ϭ 7 min) followed by monkey liver cytosol (217 min).…”

Section: Downloaded Frommentioning

confidence: 96%

See 1 more Smart Citation

A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase

et al. 2012

View full text Add to dashboard Cite

ABSTRACT:The ring oxidation of 2H-oxazole, or C2-unsubstituted oxazole, to 2-oxazolone, a cyclic carbamate, was observed on various 4-or 5-substituted oxazoles. Using 5-(3-bromophenyl)oxazole as a model compound, its 2-oxazolone metabolite M1 was fully characterized by liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance. The reaction mainly occurred in the liver cytosolic fraction without the requirement of cytochrome P450 enzymes and cofactor NADPH. Investigations into the mechanism of formation of 2-oxazolone using various chemical inhibitors indicated that the reaction was primarily catalyzed by aldehyde oxidase and not by xanthine oxidase. In addition, cytosol incubation of 5-(3-bromophenyl)oxazole in the medium containing H 2 18 O led to the 18 O incorporation into M1, substantiating the reaction mechanism of a typical molybdenum hydroxylase. The rank order of liver cytosols for the 2-oxazolone formation was mouse > monkey Ͼ Ͼ rat and human liver cytosol, whereas M1 was not formed in dog liver cytosol. Because the reaction was observed with a number of 4-or 5-substituted 2H-oxazoles in mouse liver cytosols, 2H-oxazoles represent a new substrate chemotype for ring oxidation catalyzed by aldehyde oxidase.

show abstract

Section: Downloaded Fromsupporting

confidence: 90%

Section: Downloaded Frommentioning

confidence: 96%

A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase

et al. 2012

View full text Add to dashboard Cite

show abstract

“…SKF525-A, a reported inhibitor of AO, did not inhibit the formation of this metabolite in monkey cytosol (95% of control), whereas M11 formation was inhibited by SKF525-A in human cytosol (62% of control). It should be noted that inhibition of molybdenum hydroxylases is less understood than is the case with P450s, and the same AO inhibitor can exhibit different inhibitory potentials among species and for different marker substrates (Sahi et al, 2008). Together, these data suggested that AO and not XO is the enzyme responsible for the formation of the M11 metabolite in the monkey and human.…”

Section: Resultsmentioning

confidence: 99%

Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications

Diamond¹,

Boer²,

Maduskuie³

et al. 2010

Drug Metab Dispos

127

110

View full text Add to dashboard Cite

ABSTRACT:An investigation was conducted to follow up on the apparent speciesdependent toxicity reported for 6-(6- was generated by monkey and human liver S-9, and to a lesser extent by rat S-9, whereas M11 was absent in dog S-9 incubations. We confirmed the identity of M11 as 2-quinolinone-SGX523. Experiments with various molybdenum hydroxylase inhibitors showed that aldehyde oxidase (AO), and not xanthine oxidase, metabolized SGX523 to M11 in monkey and human liver cytosol. In addition, the oxygen incorporated into M11 was derived from water rather than atmospheric oxygen, corroborating M11 formation via AO. After oral dosing in monkeys, metabolite profiling of plasma and urine showed that SGX523 was indeed metabolized to M11 and its N-demethyl analog (M8). In urine, M11 levels were ϳ70-fold greater than that of SGX523, and the solubility of M11 in urine was only 3% of that of SGX523. In summary, SGX523 is metabolized by AO in a species-specific manner to a markedly less-soluble metabolite, M11. We propose that M11 is likely involved in the observed obstructive nephropathy reported in clinical studies. Moreover, this study illustrates the need to conduct thorough metabolic evaluations early in drug development to select the most relevant nonclinical species for toxicological evaluation.(There has been much effort during the past several years to develop targeted therapy for oncological indications to improve efficacy and tolerability. One compelling therapeutic target is mesenchymal-epithelial transition factor (c-MET), a receptor tyrosine kinase implicated in the control of multiple signal transduction pathways involved in tumor growth and metastasis (Liu et al., 2008). 6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo [4,3-b]pyridazin-3-ylthio)quinoline (SGX523) is an orally bioavailable, potent, and selective small molecule inhibitor of c-MET, and this compound was one of the first selective c-MET inhibitors to be evaluated in patients (Buchanan et al., 2009). Because the microsomal metabolism profile of SGX523 was similar among rats, dogs, monkeys, and humans, investigational new drug-enabling studies were conducted in rats and dogs (Burley, 2009). The SGX523 Phase I study was started at a dose of 40 mg in patients. After escalating to doses Ͼ80 mg of SGX523 in patients, acute renal failure was observed as evidenced by increased serum creatinine. The analysis of samples from the discontinued clinical trial revealed a metabolism profile different from that of the preclinical species studied. Subsequent in vivo studies using monkeys showed obstructive nephropathy with intratubular crystal formation, consistent with human data, but the mechanism involved in the toxicity has not been reported (Burley, 2009). In an effort to better understand this apparent species difference in metabolism and the consequent development of drug-induced crystal nephropathy in a species-specific manner, we prepared SGX523 and studied its metabolite profile. Materials and MethodsChemicals and Reagents. All the chemicals, including all...

show abstract

“…A panel of widely used AO inhibitors with different chemical structures and properties, including raloxifene (Obach, 2004), DCPIP (Barr and Jones, 2011), menadione (Johns, 1967;Sahi et al, 2008;Barr and Jones, 2011), and b-estradiol (Johns et al, 1969;Barr and Jones, 2011), inhibited GDC-0834 metabolism (formation of M1) with low single-digit micromolar IC 50 values (Table 1). There was also evidence for CES-mediated amide hydrolysis in HLC (and DLC and human blood and plasma; see discussion to follow).…”

Section: Discussionmentioning

confidence: 99%

A Novel Reaction Mediated by Human Aldehyde Oxidase: Amide Hydrolysis of GDC-0834

et al. 2015

View full text Add to dashboard Cite

GDC-0834, a Bruton's tyrosine kinase inhibitor investigated as a potential treatment of rheumatoid arthritis, was previously reported to be extensively metabolized by amide hydrolysis such that no measurable levels of this compound were detected in human circulation after oral administration. In vitro studies in human liver cytosol determined that GDC-0834was rapidly hydrolyzed with a CL int of 0.511 ml/min per milligram of protein. Aldehyde oxidase (AO) and carboxylesterase (CES) were putatively identified as the enzymes responsible after cytosolic fractionation and mass spectrometry-proteomics analysis of the enzymatically active fractions. Results were confirmed by a series of kinetic experiments with inhibitors of AO, CES, and xanthine oxidase (XO), which implicated AO and CES, but not XO, as mediating GDC-0834 amide hydrolysis. Further supporting the interaction between GDC-0834 and AO, GDC-0834 was shown to be a potent reversible inhibitor of six known AO substrates with IC 50 values ranging from 0.86 to 1.87 mM. Additionally, in silico modeling studies suggest that GDC-0834 is capable of binding in the active site of AO with the amide bond of GDC-0834 near the molybdenum cofactor (MoCo), orientated in such a way to enable potential nucleophilic attack on the carbonyl of the amide bond by the hydroxyl of MoCo. Together, the in vitro and in silico results suggest the involvement of AO in the amide hydrolysis of GDC-0834.

show abstract

Aldehyde Oxidase Activity and Inhibition in Hepatocytes and Cytosolic Fraction from Mouse, Rat,Monkey and Human

Cited by 62 publications

References 0 publications

A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase

A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase

Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications

A Novel Reaction Mediated by Human Aldehyde Oxidase: Amide Hydrolysis of GDC-0834

Contact Info

Product

Resources

About