UTL-5g Lowers Elevated Blood Levels of TNF-a and TGF-? and Increases Survival Rates in Animals Treated with LPS/D-(+)-galactosamine

Zhang, Yiguan; Tang, Yongxin; Chen, Ben; Valeriote, Frederick A.; Li, Xiaohui; Shaw, Jiajiu

doi:10.5099/aj140200128

Cited by 5 publications

(6 citation statements)

References 25 publications

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“…Further studies confirmed that UTL-5g was a prodrug that required metabolic activation to form the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX) to exert chemo-and radioprotective activity (Zhang et al, 2014). The hydrolytic conversion of UTL-5g to ISOX and 2,4-dichloroaniline (DCA) (Fig.…”

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confidence: 75%

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In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

Wu¹,

Shaw²,

Dubaisi³

et al. 2014

Drug Metab Dispos

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N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo-and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (V max ) of 11.1 nmol/min per mg and substrate affinity (K m ) of 41.6 mM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (V max /K m ) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC 50 values <50 mM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (k inact /K I ) of 0.68 and 0.51 minute, respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or timedependent inhibition of CYP1A2 in the future clinical development of UTL-5g.

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confidence: 75%

“…1), the active metabolite that exerts chemo-and radioprotective activity (Zhang et al, 2014). UTL-5g hydrolysis to equal molars of ISOX and DCA in HLM was NADPH-independent (Fig.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

Wu¹,

Shaw²,

Dubaisi³

et al. 2014

Drug Metab Dispos

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“…Both Isox and DCA from the treatment of UTL-5g by human microsome were further confirmed by LC-MS/MS [7]. Furthermore, a recent study showed that UTL-5g is both an active drug and a prodrug with Isox as the active metabolite [8]; however, UTL-5g is very quickly converted into Isox in human plasma [7]. Therefore it is of interest to investigate whether Isox by itself could be a viable drug candidate.…”

Section: Introductionmentioning

confidence: 86%

The Active Metabolite of UTL-5g, 5-Methylisoxazole-3-Carboxylic Acid, is Anti-Inflammatory and Reduces Doxorubicin-Induced Cardiac Toxicity

Zhang¹,

Tang²,

Chen³

et al. 2016

Am. J. Biomed. Sci.

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UTL-5g is a small-molecule TNF-α modulator that is anti-inflammatory in a carrageenan-induced edema animal model and chemoprotective against anticancer drug-induced side effects. Recently, it was shown that UTL-5g is a prodrug and its active metabolite is 5-methylisoxazole-3-carboxylic acid (Isox). We set out to investigate the anti-inflammatory and cardioprotective effects of Isox, and two of its esterified analogues, methyl ester (Isox-Me), and ethyl ester (Isox-Et). First, the carrageenan-induced edema animal model was employed to compare their anti-inflammatory effects. Briefly, Wistar rats were randomly divided into 5 groups and pretreated with vehicle, leflunomide, Isox, Isox-Me, and Isox-Et respectively before carrageenan treatment. The results showed that the anti-inflammatory effect of Isox was essentially the same as that of leflunomide. However, the anti-inflammatory effects of Isox-Me and Isox-Et were lower than that of Isox. In the second study, cardioprotective effects of Isox, Isox-Me, and Isox-Et on doxorubicin (DOX)induced toxicity were investigated. SD rats were randomly divided into five groups. Rats in groups 1 and 2 were pretreated with vehicle; rats in groups 3-5 were pretreated with Isox, Isox-Me, and Isox-Et respectively for 5 consecutive days. One hr after the last treatment, animals in group 2-5 were treated with DOX. Twenty four hr later, effects of test compounds on cardioprotection were examined. The results showed that Isox significantly reduced the cardiotoxicity, but Isox-Me and Isox-Et did not show much cardioprotective effect. A subsequent in vitro MTT study confirmed that Isox, but not Isox-Me or Isox-Et, protected cardiomyocytes from the injury induced by DOX. In summary, Isox is anti-inflammatory against carrageenan-induced edema and the anti-inflammatory effect of Isox is at least partially responsible for its chemoprotective effect against DOX-induced cardiac injury; esterification of Isox significantly reduces its anti-inflammatory effect and cardioprotective effect.

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“…For example, UTL-5g reduces cisplatin-induced toxicity by protecting kidney, liver, and platelets, thereby increasing the tolerance of mice for cisplatin (Shaw et al, 2013). UTL-5g increases the survival rates of mice treated with lipopolysaccharide (LPS) (Zhang et al, 2014) and reduces radiation-induced liver damage (Shaw et al, 2012). Given the critical role for macrophages in inflammation we hypothesized that UTL-5g exerts a primary anti-inflammatory effect in vivo by suppressing macrophage activation.…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation

Carruthers

Stemmer

Chen

et al. 2017

European Journal of Pharmacology

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UTL-5g is a novel small-molecule TNF-alpha modulator. It reduces cisplatin-induced side effects by protecting kidney, liver, and platelets, thereby increasing tolerance for cisplatin. UTL-5g also reduces radiation-induced acute liver toxicity. The mechanism of action for UTL-5g is not clear at the present time. A phosphoproteomic analysis to a depth of 4943 phosphopeptides and a luminescence-based transcription factor activity assay were used to provide complementary analyses of signaling events that were disrupted by UTL-5g in RAW 264.7 cells. Transcriptional activity downstream of the interferon gamma, IL-6, type 1 Interferon, TGF-β, PKC/Ca2+ and the glucocorticoid receptor pathways were disrupted by UTL-5g. Phosphoproteomic analysis indicated that hyperphosphorylation of proteins involved in actin remodeling was suppressed by UTL-5g (gene set analysis, FDR < 1%) as was phosphorylation of Stat3, consistent with the IL-6 results in the transcription factor assay. Neither analysis indicated that LPS-induced activation of the NF-κB, cAMP/PKA and JNK signaling pathways were affected by UTL-5g. This global characterization of UTL-5g activity in a macrophage cell line discovered that it disrupts selected aspects of LPS signaling including Stat3 activation and actin remodeling providing new insight on how UTL-5g acts to reduce cisplatin-induced side effects.

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UTL-5g Lowers Elevated Blood Levels of TNF-a and TGF-? and Increases Survival Rates in Animals Treated with LPS/D-(+)-galactosamine

Cited by 5 publications

References 25 publications

In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

The Active Metabolite of UTL-5g, 5-Methylisoxazole-3-Carboxylic Acid, is Anti-Inflammatory and Reduces Doxorubicin-Induced Cardiac Toxicity

Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation

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