Bioactivation of clozapine by mitochondria of the murine heart: Possible cause of cardiotoxicity

Arzuk, Ege; Karakuş, Fuat; Orhan, Hilmi

doi:10.1016/j.tox.2020.152628

Cited by 20 publications

(18 citation statements)

References 47 publications

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“…In practice, clozapine is titrated slowly to avoid adverse events, and there is case series evidence that rapid titration increases the risk of myocarditis 14,39 . Several animal studies support a direct link between rapid titration and high serum clozapine levels with cardiotoxic effects 32,40,41 . In murine models, Abdel‐Wahab et al 41 identified increased oxidative stress, inflammatory cytokines, DNA damage and apoptosis as well as attenuation of antioxidant activity correlating directly with increased clozapine dose.…”

Section: Discussionmentioning

confidence: 99%

“…Clozapine is predominantly metabolised in the liver to N-demethylated metabolites (norclozapine) and to N-oxides in reactions catalysed by CYP2D6, CYP1A2 and CYP3A4. 32 There is conflicting evidence on the impact that sodium valproate has on plasma clozapine levels. [33][34][35][36][37] Both Rajkumar et al and Diaz et al identified among 101 and 37 patients, respectively, increased plasma clozapine levels in those also taking sodium valproate.…”

Section: Discussionmentioning

confidence: 99%

“…In murine models, Abdel‐Wahab et al 41 identified increased oxidative stress, inflammatory cytokines, DNA damage and apoptosis as well as attenuation of antioxidant activity correlating directly with increased clozapine dose. In addition, in their recent study, Arzuk et al 32 further identified mitochondrial CYP enzymes present in cardiac tissue that activated clozapine metabolites and suggested that this may be the mechanism driving clozapine‐induced myocarditis. In addition, there are several other risk factors for myocarditis in the general population, which may also be relevant to those taking clozapine such as staphylococcal and streptococcal infections or exposure to coxsackievirus, parvovirus, certain medications, toxins and illicit substances 42‐45 …”

Section: Discussionmentioning

confidence: 99%

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Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Vickers

Ramineni

Malacova

et al. 2022

Acta Psychiatr Scand

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Objective: Clozapine is the most effective medication for treatment-refractory schizophrenia, but it is associated with severe cardiac adverse events including myocarditis and cardiomyopathy. To aid treatment decision-making for clinicians, patients and their carers, we conducted a systematic review and metaanalysis to identify potential risk factors for clozapine-induced myocarditis and cardiomyopathy.Methods: A systematic search was conducted of PubMed, Embase, CINAHL, Web of Science, Cochrane and PsycInfo for studies reporting myocarditis and cardiomyopathy among people on clozapine and potential risk factors. We calculated pooled effect sizes on risk factors using a random-effects meta-analytic model. Risk of publication bias was assessed using the Newcastle-Ottawa scale.Results: Seven studies met the inclusion criteria, of which six studies had quantitative data included in the meta-analysis. The odds of clozapine-induced myocarditis increased with concurrent sodium valproate use (k = 6, n = 903, pooled OR 3.58, 95% CI 1.81-7.06), but were not significantly greater with the use of quetiapine, lithium or selective serotonin reuptake inhibitors. Our qualitative review identified conflicting results reported for increasing age and higher clozapine dose as risk factors for myocarditis. No other factors, including genetic risk, sex, ethnicity, smoking, alcohol, substance abuse or cardiometabolic disease, were associated with greater odds of myocarditis. No risk factors for cardiomyopathy were identified in the literature. Conclusion: Concurrent use of sodium valproate increases the odds of clozapineinduced myocarditis. Thus, clinicians should consider the temporary cessation of sodium valproate during the initial titration phase of clozapine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Vickers

Ramineni

Malacova

et al. 2022

Acta Psychiatr Scand

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“…The activity of MDR1 and MRP2 efflux transporters was significantly reduced to accumulate or retain the calcein fluorescence intensity (green fluorescence) by applying verapamil (50 µM) or benzbromarone (10 µM), respectively (performed in HepG2 cells; data not shown). Since ketoconazole (1 µM), which was used as an inhibitor of cytochrome P450-3A4 (Arzuk et al 2020;Elsherbiny et al 2008;Greenblatt 2014;Greenblatt 2016;Greenblatt and Greenblatt 2014;Kalgutkar et al 2009;Karthik Venkatakrishnan 2000;Li et al 2014;Novotna et al 2014;Ohyama et al 2000;Pelkonen et al 2008;Vermeer et al 2016;Zhang et al 2017), had been reported to inhibit MDR1 efflux transporter with IC 50 > 6 µM (Nikulin 2017;Vermeer et al 2016), the cross-activity effect of ketoconazole (1 µM) with efflux transporter (MDR1) in HepG2 cells was also determined and no accumulation of the fluorescent substrates for efflux transporter was observed (performed in HepG2 cells; data not shown).…”

Section: Application Of Inhibitors Of Metabolic Enzymes and Membrane ...mentioning

confidence: 99%

Genotoxicity of pyrrolizidine alkaloids in metabolically inactive human cervical cancer HeLa cells co-cultured with human hepatoma HepG2 cells

2022

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Pyrrolizidine alkaloids (PAs) are secondary plant metabolites, which can be found as contaminant in various foods and herbal products. Several PAs can cause hepatotoxicity and liver cancer via damaging hepatic sinusoidal endothelial cells (HSECs) after hepatic metabolization. HSECs themselves do not express the required metabolic enzymes for activation of PAs. Here we applied a co-culture model to mimic the in vivo hepatic environment and to study PA-induced effects on not metabolically active neighbour cells. In this co-culture model, bioactivation of PA was enabled by metabolically capable human hepatoma cells HepG2, which excrete the toxic and mutagenic pyrrole metabolites. The human cervical epithelial HeLa cells tagged with H2B-GFP were utilized as non-metabolically active neighbours because they can be identified easily based on their green fluorescence in the co-culture. The PAs europine, riddelliine and lasiocarpine induced micronuclei in HepG2 cells, and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Metabolic inhibition of cytochrome P450 enzymes with ketoconazole abrogated micronucleus formation. The efflux transporter inhibitors verapamil and benzbromarone reduced micronucleus formation in the co-culture model. Furthermore, mitotic disturbances as an additional genotoxic mechanism of action were observed in HepG2 cells and in HeLa H2B-GFP cells co-cultured with HepG2 cells, but not in HeLa H2B-GFP cells cultured alone. Overall, we were able to show that PAs were activated by HepG2 cells and the metabolites induced genomic damage in co-cultured HeLa cells.

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“…Drug-induced functional and/or structural variations of cardiac mitochondria may result in myocarditis and cardiomyopathy by various approaches[ 78 ]. One possible mechanism of cardiac mitochondrial damage may involve antipsychotic bioactivation by cardiac tissue-specific microsomal CYPs and/or soluble oxidases/peroxidases, translocation of the resultant reactive metabolite to mitochondria, and alkylation of mitochondrial proteins[ 79 ], a mechanism similar to paracetamol-induced hepatoxicity[ 80 ]. Furthermore, the parent drug and/or its metabolite(s) may enter cardiac mitochondria to form nitronium ions, which localize within this organelle and consequently cause drug accumulation in the heart[ 79 ].…”

Section: Mechanisms Underlying Antipsychotics Cardiotoxicitymentioning

confidence: 99%

Antipsychotics cardiotoxicity: What's known and what's next

Li¹,

Tang²,

Li³

2021

WJP

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Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling, sometimes life-shortening adverse effects. Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns. These cardiotoxic effects range from arrhythmia to heart failure in the clinic, with myocarditis/cardiomyopathy, ischemic injuries, and unexplained cardiac lesions as the pathological bases. Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity. This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level. We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity. We propose that third-generation antipsychotics or drug adjuvant therapy, such as cannabinoid receptor modulators that confer dual benefits — i.e. , alleviating cardiotoxicity and improving metabolic disorders — deserve further clinical evaluation and marketing.

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Bioactivation of clozapine by mitochondria of the murine heart: Possible cause of cardiotoxicity

Cited by 20 publications

References 47 publications

Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Risk factors for clozapine‐induced myocarditis and cardiomyopathy: A systematic review and meta‐analysis

Genotoxicity of pyrrolizidine alkaloids in metabolically inactive human cervical cancer HeLa cells co-cultured with human hepatoma HepG2 cells

Antipsychotics cardiotoxicity: What's known and what's next

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