Inhibition of the Enzymatic Activity of Heme Oxygenases by Azole-Based Antifungal Drugs

Kinobe, Robert T.; Dercho, Ryan A.; Vlahakis, Jason Z.; Brien, James F.; Szarek, Walter A.; Nakatsu, Kanji

doi:10.1124/jpet.106.102699

Cited by 37 publications

(18 citation statements)

References 35 publications

(34 reference statements)

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“…The competitive HO inhibitor tin protoporphyrin IX (SnPP; (Drummond and Kappas, 1981) and the non-competitive HO inhibitor ketoconazole (Keto; Kinobe et al, 2006), both damped SCN PER2∷LUC rhythms relative to controls (Figs. 4 and S2; p’s < .05).…”

Section: Resultsmentioning

confidence: 99%

Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants

2009

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The hypothalamic suprachiasmatic nucleus (SCN), which in mammals serves as the master circadian pacemaker by synchronizing autonomous clocks in peripheral tissues, is composed of coupled single-cell oscillators that are driven by interlocking positive/negative transcriptional/translational feedback loops. Several studies have suggested that heme, a common prosthetic group that is synthesized and degraded in a circadian manner in the SCN, may modulate the function of several feedback loop components, including the REV-ERB nuclear receptors and PERIOD2 (PER2). We found that ferric heme (hemin, 3-100 μM) dose-dependently and reversibly damped luminescence rhythms in SCN explants from mice expressing a PER2∷LUCIFERASE (PER2∷LUC) fusion protein. Inhibitors of heme oxygenases (HOs, which degrade heme to biliverdin, carbon monoxide, and iron) mimicked heme’s effects on PER2 rhythms. In contrast, heme and HO inhibition did not damp luminescence rhythms in thymus and esophagus explants and had only a small effect on PER2∷LUC damping in spleen explants, suggesting that heme’s effects are tissue-specific. Analysis of the effects of heme’s degradation products on SCN PER2∷LUC rhythms indicated that they probably were not responsible for heme’s effects on rhythms. The heme synthesis inhibitor N-methylprotoporphyrin IX (NMP) lengthened the circadian period of SCN PER2∷LUC rhythms by about an hour. These data are consistent with an important role for heme in the circadian system.

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Section: Resultsmentioning

confidence: 99%

Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants

2009

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“…One interesting aspect is the fact that the bacterial HO inhibitors identified by Furci et al (2007) bear close structural similarities to some of the imidazole-based inhibitors of mammalian HO activity characterised in our laboratory (Vlahakis et al 2005;Kinobe et al 2006a). Moreover, these imidazole-based mammalian and bacterial HO inhibitors are also structurally similar to azole-based antifungal drugs, including ketoconazole, sulconazole, and terconazole, which were identified as potent inhibitors of mammalian HO-1 and HO-2 (Kinobe et al 2006b). Because the inhibition of HO-1 and HO-2 activity by the imidazole-based antifungal drugs was observed at therapeutically relevant concentrations, it is plausible that inhibition of mammalian HO activity may play a role in some of the pharmacologic actions of these antimycotic drugs.…”

Section: Ho Activity In Infectionsmentioning

confidence: 92%

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Kinobe

Dercho

Nakatsu

2008

Can. J. Physiol. Pharmacol.

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The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This 'next generation' of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO.

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“…To block HO-activity during curcumin + NAC treatment we used the previously described specific non-porphyrin HO-activity inhibitor QC-15 at a dose of 50 μM [22, 23]. Since we observed that 50-μM SnMP in combination with 25-μM curcumin affected HO-1 expression and therefore could act as a possible confounder, we opted for the QC-15 inhibitor to study the effect of HO-activity in all experiments where 25-μM curcumin was used.…”

Section: Methodsmentioning

confidence: 99%

Curcumin‐induced fibroblast apoptosis and in vitro wound contraction are regulated by antioxidants and heme oxygenase: implications for scar formation

Scharstuhl

Mutsaers

Pennings

et al. 2009

J Cellular Molecular Medi

100

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Fibroblast apoptosis plays a crucial role in normal and pathological scar formation and therefore we studied whether the putative apoptosis-inducing factor curcumin affects fibroblast apoptosis and may function as a novel therapeutic. We show that 25-μM curcumin causes fibroblast apoptosis and that this could be inhibited by co-administration of antioxidants N-acetyl-l-cysteine (NAC), biliverdin or bilirubin, suggesting that reactive oxygen species (ROS) are involved. This is supported by our observation that 25-μM curcumin caused the generation of ROS, which could be completely blocked by addition of NAC or bilirubin. Since biliverdin and bilirubin are downstream products of heme degradation by heme oxygenase (HO), it has been suggested that HO-activity protects against curcumin-induced apoptosis. Interestingly, exposure to curcumin maximally induced HO-1 protein and HO-activity at 10–15 μM, whereas, at a concentration of >20-μM curcumin HO-1-expression and HO-activity was negligible. NAC-mediated inhibition of 25-μM curcumin-induced apoptosis was demonstrated to act in part via restored HO-1-induction, since the rescuing effect of NAC could be reduced by inhibiting HO-activity. Moreover pre-induction of HO-1 using 5-μM curcumin protected fibroblasts against 25-μM curcumin-induced apoptosis. On a functional level, fibroblast-mediated collagen gel contraction, an in vitro wound contraction model, was completely prevented by 25-μM curcumin, while this could be reversed by co-incubation with NAC, an effect that was also partially HO-mediated. In conclusion, curcumin treatment in high doses (>25 μM) may provide a novel way to modulate pathological scar formation through the induction of fibroblast apoptosis, while antioxidants, HO-activity and its effector molecules act as a possible fine-tuning regulator.

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Inhibition of the Enzymatic Activity of Heme Oxygenases by Azole-Based Antifungal Drugs

Cited by 37 publications

References 35 publications

Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants

Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Curcumin‐induced fibroblast apoptosis and in vitro wound contraction are regulated by antioxidants and heme oxygenase: implications for scar formation

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