Small Heterodimer Partner Regulates Circadian Cytochromes p450 and Drug-Induced Hepatotoxicity

Zhang, Tianpeng; Yu, Fangjun; Guo, Lianxia; Chen, Min; Yuan, Xue; Wu, Baojian

doi:10.7150/thno.28676

Cited by 68 publications

(55 citation statements)

References 52 publications

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“…Our study showed that mice are sensitive to acetaminophen‐induced liver injury at night and that a change in Cyp2e1 activity was consistent with the sensitivity against acetaminophen‐induced liver injury (Figure ). These results are consistent with the findings of a previous report (Zhang et al, ). Acetaminophen is converted to NAPQI by Cyps (Cyp2e1, Cyp1a2 and Cyp3a), which then causes hepatotoxicity in mice.…”

Section: Discussionsupporting

confidence: 94%

“…A (Figure c, d). Our results are consistent with those reported by other groups (Liu, Li, Xu, Xu, & Liu, ; Matsunaga et al, ; T. Zhang et al, ; Y.‐K. J. Zhang, Yeager, & Klaassen, ) and demonstrate that sensitivity to acetaminophen‐induced liver injury in mice is dependent on the time of administration.…”

Section: Discussionsupporting

confidence: 93%

“…B′ (Figure h–l). No different expression of Cyp3a11 in primary cultured hepatocytes between at cZT 2 and at cZT 14 was consistent with other groups in mice (Zhang et al, ). The drugs metabolized by CYP3a enzymes may not be affected by circadian rhythm in our experimental scheme.…”

Section: Discussionsupporting

confidence: 90%

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Acetaminophen‐induced hepatotoxicity of cultured hepatocytes depends on timing of isolation from light‐cycle controlled mice

et al. 2020

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Most physiological changes follow a daily cycle in animals because their circadian rhythm is adjusted to and synchronized with sunlight. In particular, the circadian rhythm affects liver functions, including pharmacokinetics and metabolism. The influence of circadian rhythm has not been included in hepatotoxicity assays used in drug discovery and development. In this study, the contribution of circadian rhythm was investigated in acetaminophen‐induced hepatotoxicity in mice and primary cultured hepatocytes. Hepatotoxicity was induced via the intraperitoneal administration of acetaminophen to a greater extent at night than during the day in mice. The sensitivity of acetaminophen‐induced hepatotoxicity was consistent with the expression levels of acetaminophen‐metabolizing enzyme and circadian genes. The host‐derived circadian rhythm was still evident in the primary cultured hepatocytes within a day after their isolation from the liver. Primary cultured hepatocytes isolated at night were significantly more sensitive to acetaminophen than those isolated during the day. The sensitivity toward acetaminophen‐induced hepatotoxicity depended on the circadian rhythm of the expression of acetaminophen‐metabolizing genes and intracellular glutathione levels in primary cultured hepatocytes. These results obtained from cultured cells correspond to those in mice, suggesting that the timing of hepatocyte isolation is important when investigating drug metabolism and toxicity tests in culture.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 93%

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Acetaminophen‐induced hepatotoxicity of cultured hepatocytes depends on timing of isolation from light‐cycle controlled mice

et al. 2020

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“…In addition, REV‐ERBα/β play important roles in regulation of many other physiological processes including cell differentiation, inflammation, lipid, and glucose metabolism (Cho et al, ; Gibbs et al, ; J. Wang & Lazar, ). Our recent studies also suggest a critical role for REV‐ERBα in regulation of DMEs including CYP2B10 and carboxylesterases (Zhang et al, ; Zhao, Zhang, Yu, Guo, & Wu, ).…”

Section: Introductionmentioning

confidence: 73%

“…For instance, CYP2B10‐mediated detoxification of pentobarbital and cyclophosphamide is modulated by three clock output genes D‐site binding protein ( DBP ), hepatic leukaemia factor ( HLF ), and thyrotroph embryonic factor ( TEF ; Gachon, Olela, Schaad, Descombes, & Schibler, ). The circadian gene small heterodimer partner ( SHP ) participates in regulating toxicities of paracetamol, aflatoxin B1, and mitoxantrone (T. Zhang et al, ). Also, the two clock output genes HLF and E4BP4 control the diurnal rhythms of expression of the intestinal drug transporter P‐gp (ABCB1) and of digoxin accumulation (Murakami, Higashi, Matsunaga, Koyanagi, & Ohdo, ).…”

Section: Introductionmentioning

confidence: 99%

Role of the CLOCK protein in liver detoxification

Zhao

Deng

et al. 2019

British J Pharmacology

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Background and Purpose: Whether and how circadian clock proteins regulate drug detoxification are not known. Here, we have assessed the effects of CLOCK (a core circadian clock protein) on drug metabolism and detoxification. Experimental Approach: Regulation by CLOCK protein of drug-metabolizing enzymes was assessed using Clock knockout (Clock −/− ) mice and Hepa-1c1c7/AML-12 cells. The relative mRNA and protein levels were determined by qPCR and Western blotting respectively. Toxicity and pharmacokinetic experiments were performed with Clock −/− and wild-type mice after intraperitoneal injection of coumarin or cyclophosphamide. Transcriptional gene regulation was investigated using luciferase reporter, mobility shift, and chromatin immunoprecipitation (ChIP) assays. Key Results: Clock deletion disrupted hepatic diurnal expressions of a number of drug-metabolizing enzymes in mice. In particular, CYP2A4/5 expressions were markedly down-regulated, whereas CYP2B10 was up-regulated. Positive regulation of Cyp2a4/5 and negative regulation of Cyp2b10 by CLOCK were confirmed in Hepa-1c1c7 and AML-12 cells. Based on a combination of luciferase reporter, mobility shift, and ChIP assays, we found that CLOCK activated Cyp2a4/5 transcription via specific binding to E-box elements in promoter region and repressed Cyp2b10 transcription through REV-ERBα/β (two target genes of CLOCK and transcriptional repressors of Cyp2b10). Furthermore, Clock ablation sensitized mice to coumarin toxicity by down-regulating CYP2A4/5-mediated metabolism (a detoxification pathway) and to cyclophosphamide toxicity by up-regulating CYP2B10-mediated metabolism (generating the toxic metabolite 4-hydroxycyclophosphamide).Conclusion and Implications: CLOCK protein regulates metabolism by the cytochrome P450 family and drug detoxification. The findings improve our understanding of the crosstalk between circadian clock and drug detoxification.

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Influence of circadian rhythm on drug metabolism in 3D hepatic spheroids

Narayanan

Rodrigues

Dordick

2022

Biotech & Bioengineering

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Circadian rhythms are characterized as oscillations that fluctuate based on a 24 h cycle and are responsible for regulation of physiological functions. While the internal clock synchronizes gene expression using external cues like light, a similar synchronization can be induced in vitro by incubating the cells with an increased percentage of serum followed by its rapid removal. Previous studies have suggested that synchronization of HepG2 cell line induced the rhythmic expression of drugmetabolizing enzymes (DME) most specifically the cytochrome P450 enzymes.However, there is a lack of evidence demonstrating the influence of threedimensional microenvironment on the rhythmicity of these genes. To understand this interplay, gene expression of the circadian machinery and CYP450s were compared using the model human hepatocarcinoma cell line, HepG2. Upon serum shock synchronization, gene and protein expression of core clock regulators was assessed and rhythmic expression of these genes was demonstrated. Further insight into the interrelations between various gene pairs was obtained using statistical analysis. Using RNA sequencing, an in-depth understanding of the widespread effects of circadian regulation on genes involved in metabolic processes in the liver was obtained. This study aids in the better understanding of chronopharmacokinetic events in humans using physiologically relevant 3D culture systems.

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Small Heterodimer Partner Regulates Circadian Cytochromes p450 and Drug-Induced Hepatotoxicity

Cited by 68 publications

References 52 publications

Acetaminophen‐induced hepatotoxicity of cultured hepatocytes depends on timing of isolation from light‐cycle controlled mice

Acetaminophen‐induced hepatotoxicity of cultured hepatocytes depends on timing of isolation from light‐cycle controlled mice

Role of the CLOCK protein in liver detoxification

Influence of circadian rhythm on drug metabolism in 3D hepatic spheroids

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