Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

Harkitis, Panagiotis; Daskalopoulos, Evangelos P.; Malliou, Foteini; Lang, Matti A.; Marselos, Marios; Fotopoulos, Andreas; Albucharali, G.; Konstandi, Maria

doi:10.1371/journal.pone.0128708

Cited by 19 publications

(22 citation statements)

References 69 publications

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“…It is found that the antagonists of D2 dopaminergic receptors interfere with the regulation if CYP2C enzymes. 85,86 This can support the link between interfering dopamine transportation and CYP2C19 activity highlighted in the rules. Secondly is the combination of CD40 with IL-8 cytokine.…”

Section:  Combined Bioactivity Readoutsmentioning

confidence: 65%

Understanding Conditional Associations between ToxCast in Vitro Readouts and the Hepatotoxicity of Compounds Using Rule-Based Methods

Mahmoud

Svensson

Zoufir

et al. 2019

Chem. Res. Toxicol.

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Current in vitro models for hepatotoxicity commonly suffer from low detection rates due to incomplete coverage of bioactivity space. Additionally, in vivo exposure measures such as Cmax are used for hepatotoxicity screening which are unavailable early on. Here we propose a novel rule-based framework to extract interpretable and biologically meaningful multi-conditional associations to prioritize in vitro endpoints for hepatotoxicity and understand the associated physicochemical conditions. The data used in this study was derived for 673 compounds from 361 ToxCast bioactivity measurements and 29 calculated physicochemical properties against two lowest effective levels (LEL) of rodent hepatotoxicity from ToxRefDB, namely 15mg/kg/day and 500mg/kg/day. In order to achieve 80% coverage of toxic compounds, 35 rules with accuracies ranging from 96% to 73% using 39 unique ToxCast assays are needed at a threshold level of 500mg/kg/day, whereas to describe the same coverage at a threshold of 15mg/kg/day 20 rules with accuracies of between 98% and 81% were needed, comprising 24 unique assays. Despite the 33-fold difference in dose levels, we found relative consistency in the key mechanistic groups in rule clusters, namely i) activities against Cytochrome P, ii) immunological responses, and iii) nuclear receptor activities. Less specific effects, such as oxidative stress and cell cycle arrest, were used more by rules to describe toxicity at the level of 500mg/kg/day. Although the endocrine disruption through nuclear receptor activity formulated an essential cluster of rules, this bioactivity is not covered in four commercial assay setups for hepatotoxicity. Using an external set of 29 drugs with drug-induced liver injury (DILI) labels, we found that the likelihood of liver toxicity increases as compounds' promiscuity over important assays increases. In vitro-in vivo associations were also improved by incorporating physicochemical properties especially for the potent, 15mg/kg/day toxicity level, as well for assays describing nuclear receptor activity and phenotypic changes. The most frequently used physicochemical properties, predictive for hepatotoxicity in combination with

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Section:  Combined Bioactivity Readoutsmentioning

confidence: 65%

Understanding Conditional Associations between ToxCast in Vitro Readouts and the Hepatotoxicity of Compounds Using Rule-Based Methods

Mahmoud

Svensson

Zoufir

et al. 2019

Chem. Res. Toxicol.

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“…Dopaminergic systems regulate the release of several hormones, including growth hormone (GH), thyroid hormones, insulin, glucocorticoids, and prolactin (PRL), which play significant roles in the regulation of various CYP450 enzymes. Inhibition of dopamine D2-receptors with sulpiride (SULP) significantly repressed the constitutive and benzo[a]pyrene (B[a]P)-induced cyp1a1, cyp1a2, and cyp1b expression in the rat liver, which appears to be mediated by activation of the insulin/PI3K/AKT pathway [38]. Injection of 5,7-DHT decreased serotonin concentration in the brain, followed by a significant rise in the levels of growth hormone, corticosterone, and testosterone, and a drop in triiodothyronine concentration in the serum.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

Zhong

Chen

et al. 2018

Toxins

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Solasonine was reported to inhibit tumour cell growth in several different models. The in vivo toxicity of solasonine, the effects of genetic background on its toxicity, and its possible roles in regulating the expression of cyp450 family genes were still unclear and required characterisation. Here, Horn’s assays were performed on male mice from four different strains, and the expression of cyp450 family genes in their livers was examined by RT-PCR and ELISA. Mice treated by intraperitoneal injection with high levels of solasonine showed immediate post-excitatory depression, intraperitoneal tissue adhesion, and dissolving of cells in the liver. Furthermore, these four mouse strains showed different toxicological sensitivity to solasonine. The strains, in decreasing order of LD50 value, rescuing speed of body weight, and more severe pathological symptoms, were KM, ICR, C57BL/6, and BALB/c. Interestingly, more cyp450 genes were downregulated at the mRNA and/or protein level in the livers of male mice from C57BL/6 or BALB/c strains than those from KM or ICR strains. These results suggest that (1) Solasonine has hepatic toxicity and downregulates cyp450 genes expression at transcriptional and/or post-transcriptional levels; (2) Genetic background is an important factor which can affect the in vivo toxicity; (3) Downregulation of cyp450 gene expression in the liver may be a clue to help understand whether or not a given strain is sensitive to solasonine; (4) Influences on the expression of cyp450 genes should be considered when using solasonine alone, or in combination with other drugs.

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“…CGS21680 has been shown to also bind to adenosine A 1 receptors at a 140-fold higher concentration than for A 2A receptors . Information regarding the hepatic metabolism of these compounds has not be reported, though L-741,626 significantly inhibits the gene expression of many cytochrome P450 enzymes including CYP1A1, CYP1A2, CYP1B1, CYP2C11, CYP2D1, CYP2D2, CYP2E1, CYP3A1, and CYP3A2 (Daskalopoulos et al, 2012;Harkitis et al, 2015).…”

Section: Pharmacological Reduction Of Repetitive Behaviorsmentioning

confidence: 99%

Targeting Dopamine D₂, Adenosine A_2A, and Glutamate mGlu₅ Receptors to Reduce Repetitive Behaviors in Deer Mice

Lewis

Primiani

Muehlmann

2019

J Pharmacol Exp Ther

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Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D 2 , adenosine A 2A , and glutamate mGlu 5 receptors. These receptors function both individually and as receptor heteromers. We found that only the triple drug cocktail (L-741,6261CGS216801CDPPB) that was designed to increase striatal indirect basal ganglia pathway cell function reduced repetitive behavior in adult male deer mice. No single drug or double drug combinations were effective at selectively reducing repetitive behavior. We found this triple drug cocktail reduced repetitive behavior in both short-acting and long-acting formulations and was effective throughout 7 days of daily administration. Conversely, another triple drug cocktail (quinpirole1SCH582611MTEP) that was designed to further reduce striatal indirect basal ganglia pathway cell function caused a significant increase in repetitive behavior. Significant and behaviorally selective effects on repetitive behavior were only achieved with the triple drug cocktails that included doses of L-741,626 and quinpirole that have off-target effects (e.g., dopamine D 3 receptors). These data further a role for decreased indirect basal ganglia pathway activation in repetitive behavior and suggest that targeting these receptors and/or heteromeric complexes on the indirect pathway neurons of the striatum may offer pharmacotherapeutic benefit for individuals with repetitive behavior disorders.

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Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

Cited by 19 publications

References 69 publications

Understanding Conditional Associations between ToxCast in Vitro Readouts and the Hepatotoxicity of Compounds Using Rule-Based Methods

Understanding Conditional Associations between ToxCast in Vitro Readouts and the Hepatotoxicity of Compounds Using Rule-Based Methods

In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

Targeting Dopamine D₂, Adenosine A_2A, and Glutamate mGlu₅ Receptors to Reduce Repetitive Behaviors in Deer Mice

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Dopamine D2-Receptor Antagonists Down-Regulate CYP1A1/2 and CYP1B1 in the Rat Liver

Cited by 19 publications

References 69 publications

Understanding Conditional Associations between ToxCast in Vitro Readouts and the Hepatotoxicity of Compounds Using Rule-Based Methods

Understanding Conditional Associations between ToxCast in Vitro Readouts and the Hepatotoxicity of Compounds Using Rule-Based Methods

In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains

Targeting Dopamine D2, Adenosine A2A, and Glutamate mGlu5 Receptors to Reduce Repetitive Behaviors in Deer Mice

Contact Info

Product

Resources

About

Targeting Dopamine D₂, Adenosine A_2A, and Glutamate mGlu₅ Receptors to Reduce Repetitive Behaviors in Deer Mice