Comparative Biochemical and Morphometric Changes Associated with Induction of the Hepatic Mixed Function Oxidase System in the Rat

Howard, Monica O.; Newton, John F.; Qualls, Charles W.; Yodis, Lee Ann P.; Ventre, John

doi:10.1177/019262339101900205

Cited by 15 publications

(6 citation statements)

References 10 publications

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“…Pharmacological inhibition of MAPK, particularly of p38 MAPK, has been investigated extensively as a potential therapeutic approach to a number of human diseases including cancer, autoimmune diseases, stroke, and chronic inflammatory conditions [23]. Actually, the first-generation pyridinyl imidazole inhibitor, SB 203580 was a representative pharmacologic agent to inhibit p38 MAPK and was, however, found to be hepatotoxic and potential carcinogens; thus, the use in the clinic has been hampered [24][25][26]. Therefore, major challenges in potential application of p38 MAPK inhibitors as anti-inflammatory therapeutics are first of all drugs specificity and, secondly, potential side effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p38 MAPK Reduces Expression of Vascular Endothelial Growth Factor in Allergic Airway Disease

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Inhibition of p38 MAPK Reduces Expression of Vascular Endothelial Growth Factor in Allergic Airway Disease

et al. 2012

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“…Furthermore, high concentrations of priority polycyclic aromatic hydrocarbons (PAHs) were determined in sediments from several sites along the Upper Danube River (maximum sum of 16 US EPA [Environmental Protection Agency] PAHs 26 µg g -1 sediment equivalent; Keiter et al 2008). AhR agonists such as PCBs, dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), PAHs, and polychlorinated naphthalenes (PCNs) have been documented to profoundly alter liver ultrastructure (Howard et al 1991, Wu et al 1999, Strmac & Braunbeck 2002. AhR agonists like PCBs have been shown to have adverse consequences on fish health and population growth and are suspected to have been involved in several cases of fish declines (Niimi 1983, Gilbertson 1992, Monosson 1997, Fairbrother et al 1999, Whyte et al 2000, Van der Oost et al 2003.…”

Section: Reasons For Fish Decline In the Danube Rivermentioning

confidence: 99%

Assessment of fish health status in the Upper Danube River by investigation of ultrastructural alterations in the liver of barbel Barbus barbus

Grund¹,

Keiter²,

Böttcher³

et al. 2010

Dis. Aquat. Org.

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Despite intensive efforts and tightened guidelines for improvement of water quality over the last 2 decades, declines of fish populations have been reported for several rivers around the world. The present study forms part of a comprehensive weight-of-evidence approach, which aims to identify potential causes for the decline in fish catches observed in the Upper Danube River. The major focus of the present study is the investigation of the health status of wild barbel Barbus barbus L. collected from 3 locations along the Danube River, which experienced different levels of contamination. Whereas the comparison of the condition factor (CF) of field fish with that of control fish revealed no differences, ultrastructural investigations indicated severe disturbance of hepatic cell metabolism in field fish from the more contaminated sites Rottenacker and Ehingen, compared to both control fish and field fish from the less contaminated site Riedlingen. The ultrastructural analysis provided information about reactions of e.g. the rough endoplasmic reticulum, peroxisomes, and mitochondria, indicating an impaired health status of barbel at the sampling sites Rottenacker and Ehingen. Even though a straightforward cause-effect relationship between sediment contamination and ultrastructural alterations could not be established, based on a meta-analysis and toxicity assays it may be suggested that sediment-bound xenobiotics at least partly account for the hepatocellular changes. A relationship between impaired fish health status and the decline of fish catches along the Upper Danube River cannot be excluded.

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“…Unfortunately, progression of SK&F 86002 and SB 203580 into the clinical practice was hampered by severe toxicological properties. Thus, these first generation inhibitors have been found to be hepatotoxic and potential carcinogens [43,44]. The origin of these toxic effects has been related to their potent induction of some cytochrome P-450 isoenzymes [44,45], a profile which had previously been recognized as an indicator of potential carcinogenesis [46].…”

Section: Inhibitors Of P38 Map Kinasementioning

confidence: 99%

“…Indeed, the strong H bond established between the pyridine nitrogen and the amide NH of Met 109 is a key determinant of binding affinity, common to all pyridinyl imidazole inhibitors of p38. On the other side, the hepatic changes leading to induction of P-450 enzymes and subsequent toxicity of these first generation pyridinyl imidazoles were related to their potent in vitro inhibition of some cytochrome P-450 isoenzymes [43]. In the origin of this inhibition, interaction of the pyridine N with the ferric ion of the heme cofactor of P-450 has been regarded as one possible participating mechanism [64].…”

Section: Pyrimidinyl Imidazolesmentioning

confidence: 99%

Structure-Activity Relationships of p38 Mitogen-Activated Protein Kinase Inhibitors

Bolós

2005

MRMC

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Rheumatoid arthritis and other chronic inflammatory diseases constitute a major therapeutic challenge, usually not sufficiently met by the classical antiinflammatory medications. Recent research efforts provided new insights into the molecular basis of these pathologies and disclosed new opportunities for developing improved drugs directed to the chemical mediators of the disease. The enzyme p38 MAP kinase plays a central role in the signal transduction cascade that leads to the production of both the proinflammatory cytokines, TNF-alpha and IL-1 beta, thus representing an attractive therapeutic target for novel antiinflammatory therapies. A number of p38 inhibitors belonging to different structural families have been developed as potential antiinflammatory drugs, and some of them progressed into clinical trials. The initial pyridinyl imidazole inhibitors contributed to the identification and characterization of p38 MAP kinase as the molecular target of these new drugs, and were found to act as competitive inhibitors at the ATP binding site of the enzyme. A number of variations in the pyridine and imidazole rings were subsequently introduced. Other inhibitors structurally unrelated to the pyridinylimidazoles have also been developed, such as the pyridopyridazinones, diaryl ureas, aminobenzophenones and aromatic amides. One of these structural classes, the N,N'-diarylureas, has been found to interact with a distinct allosteric site of p38 MAP kinase and requires a deep conformational change prior to binding.

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Comparative Biochemical and Morphometric Changes Associated with Induction of the Hepatic Mixed Function Oxidase System in the Rat

Cited by 15 publications

References 10 publications

Inhibition of p38 MAPK Reduces Expression of Vascular Endothelial Growth Factor in Allergic Airway Disease

Inhibition of p38 MAPK Reduces Expression of Vascular Endothelial Growth Factor in Allergic Airway Disease

Assessment of fish health status in the Upper Danube River by investigation of ultrastructural alterations in the liver of barbel Barbus barbus

Structure-Activity Relationships of p38 Mitogen-Activated Protein Kinase Inhibitors

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