Alterations of Cytochrome P450–Mediated Drug Metabolism during Liver Repair and Regeneration after Acetaminophen-Induced Liver Injury in Mice

Bao, Yifan; Phan, Mi T.; Zhu, Junjie; Ma, Xiaochao; Manautou, José E.; Zhong, Xiao‐bo

doi:10.1124/dmd.121.000459

Cited by 17 publications

(11 citation statements)

References 35 publications

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“…Besides, the alternations of pharmacokinetic characteristics of APAP, NAPQI, APAP-gluc, and APAP-sul also intimated that Tan IIA might have an effect on the expression of specific metabolic enzymes. Since studies have shown that APAP is mainly metabolized by cytochrome P-450 enzyme system into toxic intermediate NAPQI, 49,50 it's meaningful to further investigate the effect of Tan IIA on CYPs in the process of protecting against APAP-induced liver or kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Zhang

Long

et al. 2022

Environmental Toxicology

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It's known that APAP overdose often leads to hepatotoxicity and nephrotoxicity. In the present study, we investigated the preventative effect of Tan IIA on APAP‐induced nephrotoxicity. Mice were orally administrated with Tan IIA (10 or 30 mg/kg/day) for 1 week and subsequently gavaged with 200 mg/kg of APAP. Tan IIA reduced APAP‐induced nephrotoxicity as evidenced by histopathological evaluation and serum creatinine levels. Tan IIA pretreatment promoted the efflux of the toxic intermediate metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI), thus reduced its injury to mouse kidney. After Tan IIA pretreatment, a remarkable increase in mRNA and protein expression of Nrf2 and its target genes Mrp2 and Mrp4 was observed in Nrf2+/+ mice kidneys, however, no obvious change of Mrp2 and Mrp4 mRNA and protein expression was detected in Nrf2−/− mice kidneys. HK‐2 cells were used for exploring the roles of Tan IIA in the Nrf2‐MRPs pathway in vitro. Consistently, Tan IIA up‐regulated the Nrf2‐MRPs pathway and promoted the nuclear Nrf2 accumulation in HK‐2 cells. Collectively, our findings suggested that Tan IIA facilitated the clearance of toxic intermediate metabolite NAPQI from the kidney through upregulation of the Nrf2‐MRP2/4 pathway, thereby, performing preventive effects against APAP‐induced nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Zhang

Long

et al. 2022

Environmental Toxicology

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“…Interestingly, a dose‐dependent decrease in mRNA level of CYP3A11, the murine ortholog of human CYP3A4 enzyme, was observed in a mouse model of acetaminophen‐induced acute liver injury. 50 It is noteworthy that changes in abundance and/or activity of CYP enzymes related to acute liver injury, the suppression effect of proinflammatory cytokines and interactions with comedications may all contribute to the net in vivo phenotype of the enzymes in patients with SARS‐CoV‐2 infection. A meta‐analysis comparing in vitro activity and/or protein level of a range of CYP enzymes between healthy individuals and patients with cancer led to inconclusive results.…”

Section: Discussionmentioning

confidence: 99%

“…Despite accumulating evidence of lower abundances of many CYP and non‐CYP enzymes in chronic liver impairment, 48,49 the corresponding data from patients with acute liver failure is lacking. Interestingly, a dose‐dependent decrease in mRNA level of CYP3A11, the murine ortholog of human CYP3A4 enzyme, was observed in a mouse model of acetaminophen‐induced acute liver injury 50 . It is noteworthy that changes in abundance and/or activity of CYP enzymes related to acute liver injury, the suppression effect of proinflammatory cytokines and interactions with comedications may all contribute to the net in vivo phenotype of the enzymes in patients with SARS‐CoV‐2 infection.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling Approaches for Patients With SARS‐CoV‐2 Infection: A Case Study With Imatinib

Adiwidjaja

Adattini

Boddy

et al. 2022

The Journal of Clinical Pharma

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, which causes coronavirus disease 2019 (COVID‐19), manifests as mild respiratory symptoms to severe respiratory failure and is associated with inflammation and other physiological changes. Of note, substantial increases in plasma concentrations of α 1 ‐acid‐glycoprotein and interleukin‐6 have been observed among patients admitted to the hospital with advanced SARS‐CoV‐2 infection. A physiologically based pharmacokinetic (PBPK) approach is a useful tool to evaluate and predict disease‐related changes on drug pharmacokinetics. A PBPK model of imatinib has previously been developed and verified in healthy people and patients with cancer. In this study, the PBPK model of imatinib was successfully extrapolated to patients with SARS‐CoV‐2 infection by accounting for disease‐related changes in plasma α 1 ‐acid‐glycoprotein concentrations and the potential drug interaction between imatinib and dexamethasone. The model demonstrated a good predictive performance in describing total and unbound imatinib concentrations in patients with SARS‐CoV‐2 infection. PBPK simulations highlight that an equivalent dose of imatinib may lead to substantially higher total drug concentrations in patients with SARS‐CoV‐2 infection compared to that in patients with cancer, while the unbound concentrations remain comparable between the 2 patient populations. This supports the notion that unbound trough concentration is a better exposure metric for dose adjustment of imatinib in patients with SARS‐CoV‐2 infection, compared to the corresponding total drug concentration. Potential strategies for refinement and generalization of the PBPK modeling approach in the patient population with SARS‐CoV‐2 are also provided in this article, which could be used to guide study design and inform dose adjustment in the future.

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“…These findings provide direction for future research on the roles and mechanisms of HNF4A-AS1 and HNF1A-AS1 under different physiologic conditions. During the time course of liver repair and regeneration after liver injury, the expression and activities of CYPs, as well as drug effectiveness and adverse drug reactions, are altered (Bao et al, 2021). Therefore, early prediction of hepatotoxicity is important for the rational use of drugs.…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells

Wang

et al. 2021

Drug Metab Dispos

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Ritonavir (RTV), a pharmacoenhancer used in anti-HIV regimens, can induce liver damage. RTV is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the liver. HNF4A antisense RNA 1 (HNF4A-AS1) and HNF1A antisense RNA 1 (HNF1A-AS1) are long noncoding RNAs that regulate the expression of pregnane X receptor (PXR) and CYP3A4. This study investigated the role and underlying mechanisms of HNF4A-AS1 and HNF1A-AS1 in RTVinduced hepatotoxicity. HNF4A-AS1 and HNF1A-AS1 were knocked down by small hairpin RNAs in Huh7 and HepG2 cells. Lactate dehydrogenase and reactive oxygen species assays were performed to assess RTV-induced hepatotoxicity. Chromatin immunoprecipitation quantitative real-time polymerase chain reaction was used to detect PXR enrichment and histone modifications in the CYP3A4 promoter. HNF4A-AS1 knockdown increased PXR and CYP3A4 expression and exacerbated RTVinduced cytotoxicity, whereas HNF1A-AS1 knockdown generated the opposite phenotype. Mechanistically, enrichment of PXR and trimethylation of histone 3 lysine 4 (H3K4me3) in the CYP3A4 promoter was increased, and trimethylation of histone 3 lysine 27 (H3K27me3) was decreased after HNF4A-AS1 knockdown. However, PXR and H3K4me3 enrichment decreased after HNF1A-AS1 knockdown. Alterations in RTV-induced hepatotoxicity caused by decreasing HNF4A-AS1 or HNF1A-AS1 were reversed by knockdown or overexpression of PXR. Increased susceptibility to RTV-induced liver injury caused by the PXR activator rifampicin was attenuated by HNF4A-AS1 overexpression or HNF1A-AS1 knockdown. Taken together, these results revealed that HNF4A-AS1 and HNF1A-AS1 modulated RTVinduced hepatotoxicity by regulating CYP3A4 expression, primarily by affecting the binding of PXR and histone modification status in the CYP3A4 promoter. SIGNIFICANCE STATEMENTHNF4A-AS1 and HNF1A-AS1, transcribed separately from neighboring antisense genes of the human transcription factor genes HNF4A and HNF1A, were identified as long noncoding RNAs that can affect RTV-induced hepatotoxicity and susceptibility to RTVinduced hepatotoxicity caused by rifampicin exposure, mainly by affecting the expression of CY3A4 via alterations in PXR enrichment and histone modification status in the CYP3A4 promoter. This discovery provides directions for further research on the mechanisms of RTV-induced liver injury.

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Alterations of Cytochrome P450–Mediated Drug Metabolism during Liver Repair and Regeneration after Acetaminophen-Induced Liver Injury in Mice

Cited by 17 publications

References 35 publications

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Tanshinone IIA prevents acetaminophen‐induced nephrotoxicity through the activation of the Nrf2‐Mrp2/4 pathway in mice

Physiologically Based Pharmacokinetic Modeling Approaches for Patients With SARS‐CoV‐2 Infection: A Case Study With Imatinib

Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells

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