Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo

Beetens, Johan; Loots, W.; Somers, Yves; Coene, M.‐C.; Clerck, Fred De

doi:10.1016/0006-2952(86)90072-9

Cited by 136 publications

(65 citation statements)

References 37 publications

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“…Ketoconazole inhibits cytochrome P450-dependent enzyme 11-hydroxylase activity, which suppresses testosterone production leading to inhibition of testosterone-dependent prostate cancer cell growth (Loose et al, 1983). Its pleiotropic inhibitory activity is evident from the fact that several P450-and non-P450-dependent enzymes (e.g., CYP3A4, UGT, aryl-hydrocarbon hydroxylase and 7-ethoxyresorufin-deethylase) are inhibited, as are other enzymes such as adenylate cyclase, 5-lipoxygenase or calmodulindependent enzymes (Beetens et al, 1986;Stalla et al, 1988;Dresser et al, 2000;Venkatakrishnan et al, 2000;Kanda and Watanabe, 2002b;Yong et al, 2005). However, ketoconazole is less well established as a transcriptional regulator of genes involved in drug or cholesterol metabolism and cyclic adenosine 3 0 ,5 0 monophosphate signaling (Takagi et al, 1989;Kim, 1992;Ellsworth et al, 1994;Kanda and Watanabe, 2002a, b).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole

et al. 2006

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Individual variation in drug metabolism is a major cause of unpredictable side effects during therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate expression of genes such as CYP (cytochrome)3A4 and MDR-1 (multi-drug resistance-1), that are involved in this process. We have found that xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, a commonly used antifungal drug. Ketoconazole mediated its effect by inhibiting the activation of NRs, human pregnenolone X receptor and constitutive androstene receptor, involved in regulation of CYP3A4 and MDR-1. The effect of ketoconazole was specific to the group of NRs that control xenobiotic metabolism. Ketoconazole disrupted the interaction of the xenobiotic receptor PXR with the co-activator steroid receptor co-activator-1. Ketoconazole treatment resulted in delayed metabolism of tribromoethanol anesthetic in mice, which was correlated to the inhibition of PXR activation and downmodulation of cyp3a11 and mdr-1 genes and proteins. These studies demonstrate for the first time that ketoconazole represses the coordinated activation of genes involved in drug metabolism, by blocking activation of a specific subset of NRs. Our results suggest that ketoconazole can be used as a pan-antagonist of NRs involved in xenobiotic metabolism in vivo, which may lead to novel strategies that improve drug effect and tolerance.

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Section: Discussionmentioning

confidence: 99%

Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole

et al. 2006

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“…Therefore, it may have a dual anti-inflammatory action in ARDS, through the inhibition of inflammatory eicosanoid synthesis, thereby directing COX products down other, less inflammatory paths e.g. those synthesising PGI 2 or PGE 1 [45]. In four trials using enteric ketoconazole to treat patients at risk of developing, or with established ARDS, a reduction in the incidence of acute respiratory failure in high-risk surgical patients and other critically ill patients was found [46][47][48].…”

Section: Lipoxygenase Metabolismmentioning

confidence: 99%

Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome

Moloney

Evans²

2003

Eur Respir J

112

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Pulmonary hypertension (PH) is a characteristic feature of the acute respiratory distress syndrome (ARDS). The magnitude of PH has been shown to correlate with the severity of lung injury in patients with ARDS independently of the severity of associated hypoxaemia and has an adverse prognostic significance.Early in the histopathological evolution of ARDS, pulmonary vasoconstriction, thromboembolism and interstitial oedema contribute to the development of PH, although pulmonary vascular remodelling probably occurs eventually. Intravenous vasodilator agents lead to an increase in intrapulmonary shunting and systemic hypotension, which can limit their therapeutic use, and have not been shown to improve survival. By contrast, rapidly metabolised vasodilators administered by inhalation induce selective pulmonary vasodilatation and decrease shunting, but again do not appear to confer a survival benefit.Research aimed at further understanding the mechanisms that underlie pulmonary hypertension, a characteristic feature of the acute respiratory distress syndrome, are expected to provide improvements in pharmacological interventions for the treatment of pulmonary hypertension in the acute respiratory distress syndrome.

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“…3a). There is evidence that it can inhibit cyclo-oxgenases 12 , phospholipase A2 14 and cytochrome P-450 1 . Accordingly, and contrary to supposition by many, NDGA is perhaps not as discriminatory a tool for identifying LOX involvement as is generally assumed to be the case.…”

Section: )79087 %2( (-7'977-32 7ipigxmsr Sj Ir^]qi Mrlmfmxsvwmentioning

confidence: 99%

Laboratory-Scale Studies of the Impact of Oxygen on Mashing

Stephenson

Biawa

Miracle

et al. 2003

Journal of the Institute of Brewing

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An assessment of the impact of oxygen and hydrogen peroxide on mashing and wort parameters has been made on a laboratory scale. Oxygen has been stridently eliminated by using an anaerobic chamber during mash analysis. Additionally the relative importance of proanthocyanidin species has been assessed by comparing the behaviour of "conventional" malt and a malt produced from a low proanthocyanidin variety. It seems that oxygen and peroxide act independently in causing the oxidation of thiolcontaining materials and polyphenols in mashes and that oxygen is not primarily exerting its impacts through the intermediacy of peroxide. The removal of thiols (presumably at least in part through the production of disulphide bridges between proteins) and of polyphenols (presumably via polymerisation) both contribute to increased wort turbidity and decreased rates of wort separation after mashing. Three inhibitors (nordihydroguaiaretic acid, ethylenediamenetetraacetate and potassium cyanide) have been employed in an attempt to differentiate between enzymic and non-enzymic events and also to identify whether lipoxygenase and peroxidase are catalysing key events. Whilst it seems that peroxidase has a key role in catalysing the oxidation of polyphenols by H 2 O 2 , it does not appear that either peroxidase or lipoxygenase is involved in the removal of measurable thiol. Nonetheless a significant proportion of the thiol elimination is likely enzyme-catalysed. We have been unable to demonstrate the production of hydroperoxides in mashes, but added hydroperoxide is undetectable, which suggests that these materials are either lost by onward conversion or by adsorption onto spent grains.

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Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo

Cited by 136 publications

References 37 publications

Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole

Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole

Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome

Laboratory-Scale Studies of the Impact of Oxygen on Mashing

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