Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450

Burkina, Viktoriia; Rasmussen, Martin Krøyer; Pilipenko, Nadezhda; Zamaratskaia, Galia

doi:10.1016/j.tox.2016.11.014

Cited by 72 publications

(37 citation statements)

References 220 publications

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“…A previous study demonstrated that the metabolism of amiodarone by CYP 3A4 significantly increased the cytotoxicity of amiodarone, and that its main metabolite, desethylamiodarone, was the major contributor of this cytotoxicity (Wu et al 2016). CYP3A4 constitutes approximately 28% of the total CYP enzymes present in human liver and plays a critical role in drug metabolism (Burkina et al 2017). Although dronedarone and amiodarone have similar structures and both are metabolized by CYP3A4, our results indicate that the impact of CYP3A4-mediated metabolism is distinctly different between the two drugs.…”

Section: Discussionmentioning

confidence: 99%

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

Chen

Bryant

et al. 2018

Arch Toxicol

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Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP3A4, 3A5, and 2D6 were the major enzymes that metabolize dronedarone, and that CYP3A7, 2E1, 2C19, 2C18, 1A1, and 2B6 also metabolize dronedarone, but to a lesser extent. Our data showed that the cytotoxicity of dronedarone was decreased in CYP3A4-, 3A5-, or 2D6-overexpressing cells compared to the control HepG2 cells, indicating that the parent dronedarone has higher potency than the metabolites to induce cytotoxicity in these cells. In contrast, cytotoxicity was increased in CYP1A1-overexpressing cells, demonstrating that CYP1A1 exerts an opposite effect in dronedarone's toxicity, comparing to CYP3A4, 3A5, or 2D6. We also studied the involvement of topoisomerase II in dronedarone-induced toxicity, and demonstrated that the overexpression of topoisomerase II caused an increase in cell viability and a decrease in γ-H2A.X induction, suggesting that suppression of topoisomerase II may be one of the mechanisms involved in dronedarone-induced liver toxicity.

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Section: Discussionmentioning

confidence: 99%

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

Chen

Bryant

et al. 2018

Arch Toxicol

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“…This arterial input function requires arterial blood samples, plasma centrifugation, and metabolites measurement. However, the metabolism of radiotracers is highly dependent on the P450 hepatic cytochromes and knowledge of the metabolite curve in primate experiments is poorly predictive of subsequent clinical studies (Burkina et al, 2017). Since arterial sampling is invasive and is not directly useful for future studies in human, we preferred therefore to restrict the current study to a test–retest and blocking study, which gave us enough knowledge about the in vivo characteristics of the tracer, while preserving an ethic reducing the intervention on the animal.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Reliability of [18F]2FNQ1P in Cynomolgus Monkeys as a PET Radiotracer for Serotonin 5-HT6 Receptors

et al. 2017

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Brain serotonin-6 receptor (5-HT6R) is the one of the most recently identified serotonin receptors. Accumulating evidence suggests that it is a potent therapeutic target for psychiatric and neurological diseases. Since [18F]2FNQ1P was recently proposed as the first fluorinated positron emission tomography (PET) radioligand for this receptor, the objective of the present study was to demonstrate its suitability for 5-HT6R neuroimaging in primates. [18F]2FNQ1P was characterized by in vitro autoradiography and in vivo PET imaging in cynomolgus monkeys. Following in vivo PET imaging, tracer binding indices were computed using the simplified reference tissue model and Logan graphical model, with cerebellum as reference region. The tracer binding reproducibility was assessed by test–retest in five animals. Finally, specificity was assessed by pre-injection of a 5-HT6R antagonist, SB258585. In vitro, results showed wide cerebral distribution of the tracer with specificity toward 5-HT6Rs as binding was effectively displaced by SB258585. In vivo brain penetration was good with reproducible distribution at cortical and subcortical levels. The automated method gave the best spatial normalization. The Logan graphical model showed the best tracer binding indices, giving the highest magnitude, lowest standard deviation and best reproducibility and robustness. Finally, 5-HT6R antagonist pre-injection significantly decreased [18F]2FNQ1P binding mainly in the striatum and sensorimotor cortex. Taken together, these preclinical results show that [18F]2FNQ1P is a good candidate to address 5-HT6 receptors in clinical studies.

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“…Moreover, the CYP expression profile and metabolic processes in pigs display many similarities with human beings. The differences and similarities between human being, mice and porcine CYP have been reviewed earlier . The human and porcine CYP superfamilies contain 57 and 59 genes (including pseudogenes), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…The differences and similarities between human being, mice and porcine CYP have been reviewed earlier. 3 The human and porcine CYP superfamilies contain 57 and 59 genes (including pseudogenes), respectively. They are grouped according to similarities in their amino acid sequence into 18 families, where CYP families 1, 2 and 3 are associated with xenobiotic metabolism.…”

mentioning

confidence: 99%

Porcine cytochrome 2A19 and 2E1

Burkina

Rasmussen

Oliinychenko

et al. 2018

Basic Clin Pharma Tox

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Cytochrome P450 (CYP) is a major group of enzymes, which conduct Phase I metabolism. Among commonly used animal models, the pig has been suggested as the most suitable model for investigating drug metabolism in human beings. Moreover, porcine CYP2A19 and CYP2E1 are responsible for the biotransformation of both endogenous and exogenous compounds such as 3-methylindole (skatole), sex hormones and food compounds. However, little is known about the regulation of porcine CYP2A19 and CYP2E1. In this MiniReview, we summarise the current knowledge about the regulation of porcine CYP2A19 and CYP2E1 by environmental, biological and dietary factors. Finally, we reflect on the need for further research, to clarify the interaction between active feed components and the porcine CYP system.

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Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450

Cited by 72 publications

References 220 publications

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

Characterization and Reliability of [18F]2FNQ1P in Cynomolgus Monkeys as a PET Radiotracer for Serotonin 5-HT6 Receptors

Porcine cytochrome 2A19 and 2E1

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