Disruption of mitochondrial activities in rabbit and human hepatocytes by a quinoxalinone anxiolytic and its carboxylic acid metabolite

Ulrich, Roger G.; Bacon, Jeffrey W.; Cramer, Clay T.; Petrella, Diane K.; Sun, E; Meglasson, M. D.; Holmuhamedov, Ekhson

doi:10.1016/s0300-483x(98)00118-8

Cited by 23 publications

(18 citation statements)

References 30 publications

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“…However, Phase I clinical trials were terminated when hepatic toxicity was observed in some human volunteers in spite of no toxicity observed after oral administration to rats, dogs or monkeys during preclinical safety studies. Furthermore, in subsequent studies a hepatic toxic syndrome in Dutch-belted rabbits and disruption of mitochondrial activities in rabbit and human after administration of panadiplon were observed [35][36].…”

Section: Tricyclic Quinoxalinonesmentioning

confidence: 99%

Chemistry, Biological Properties and SAR Analysis of Quinoxalinones

Carta

Piras²,

Loriga

et al. 2006

MRMC

228

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Quinoxaline derivatives have received much attention in recent years owing to their both biological properties and pharmaceutical applications. In this review we focus the attention on quinoxalin-2(3)-ones and quinoxalin-2,3-diones. These derivatives are particularly interesting since some of them showed antimicrobial (against several bacteria, viruses, fungi, etc), or anticancer activities. Furthermore, others are reported to be potent no-NMDA glutamate receptor antagonists, endowed with anxiolytic, deconditioning, analgesic, antispastic, antiallergic, antithrombotic activities. In this article we also report SAR studies and the most important methods of synthesis of the quinoxalin-2(3)-(di)ones.

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Section: Tricyclic Quinoxalinonesmentioning

confidence: 99%

Chemistry, Biological Properties and SAR Analysis of Quinoxalinones

Carta

Piras²,

Loriga

et al. 2006

MRMC

228

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“…To that end, male, Sprague-Dawley rats were treated with cyclopropane carboxylic acid (CPCA). Little is known concerning the toxicity associated with this compound in rats, although it has been shown to impair beta-oxidation in rabbit and human hepatocytes (Ulrich et al, 1998). Rats were also treated with butyrate, a short-chain fatty acid that is structurally similar to CPCA and has not been associated with mitochondrial impairment (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Microvesicular Steatosis Induced by a Short Chain Fatty Acid: Effects on Mitochondrial Function and Correlation with Gene Expression

et al. 2004

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Hepatotoxicity characterized by microvesicular steatosis (MVS) is characterized by an abnormal accumulation of numerous small cytoplasmic lipid droplets in hepatocytes. Fulminant or progressive cases of microvesicular steatosis may lead to liver failure and death. Experimentally, short-chain carboxylic acids are known to induce microvesicular steatosis. The identification of gene changes that correlate with MVS concomitant with biochemical and histological indices could provide a better understanding of how this toxicity occurs as well as biomarkers that could be used to avoid this toxicity in the future. Sprague-Dawley rats were dosed days with cyclopropane carboxylic acid (CPCA) a short-chain fatty acid that can induce microvesicular steatosis, and with butyrate, a short chain fatty acid that served as a negative control. CPCA initiated microvesicular steatosis while butyrate did not. In addition, CPCA inhibited beta-oxidation in a concentration-dependent manner in vitro and caused a reduction in mitochondrial respiration ex vivo; no inhibition was evident with butyrate. Microarray results showed that gene expression changes with CPCA resulted in regulation of genes involved in beta-oxidation, as well as other genes associated with mitochondrial function. Overall, these results support altered hepatic mitochondrial function as a mechanism of the toxicity induced by a short-chain fatty acid and may provide potential biomarkers for this toxicity.

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“…Quinoxaline-2-one derivatives are particularly interesting since some of them showed a variety of pharmacological properties, such as antimicrobial (Ajani et al, 2010;El-Sabbagh et al, 2009;Sanna et al, 1998;Sanna et al, 1999), antiviral (Xu et al, 2009), antifungal (Carta et al, 2002;Ingale et al, 2007;Sanna et al, 1999), anxiolytic (Ulrich et al, 1998), analgesic (Ingale et al, 2007), antiinflammatory (El-Sabbagh et al, 2009), antithrombotic (Ries et al, 2003;Willardsen et al, 2004), and antitumor (Hirai et al, 2011;Koth et al, 2007;Lawrence et al, 2001;Meyer et al, 2006) activities. Based on the computer modeling and "in vitro" studies, quinoxalin-2-ones have been proposed as potential drugs in treatments of various diseases (Carta et al, 2006).…”

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confidence: 99%