Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

ABSTRACTAcetaminophen (APAP) overdose causes hepatic injury and is major contributor to acute liver injury cases. To investigate potential roles of gut microbiota in APAP-induced liver injury, C57BL/6 mice from Jackson (JAX) or Taconic (TAC) were challenged with APAP. TAC mice were more susceptible to APAP toxicity, and this disappeared upon co-housing of JAX and TAC mice. When the cecum contents from JAX and TAC mice were transplanted to germ-free mice, the mice that received TAC gut microbiota exhibited more significant hepatotoxicity after APAP administration. Non-targeted metabolomic analysis using portal vein serum and liver tissue of the mice led to identification of 19 metabolites the levels of which are associated with JAX or TAC gut microbiota. A gut bacteria-derived metabolite phenylpropionic acid (PPA) levels in cecum contents and blood were higher in mice harboring JAX gut microbiota. PPA supplementation in drinking water alleviated APAP-induced hepatotoxicity in TAC mice. This was accompanied by reduced hepatic protein levels of cytochrome P450 (CYP) 2E1, the enzyme responsible for APAP bioactivation to a toxic metabolite. This illustrates a gut microbe-liver interaction mediated by a gut bacteria-derived metabolite in modulating drug-induced liver injury.

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Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

Case Reports in Oncological Medicine ◽

10.1155/2019/3051945 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Nicholas Gravbrot ◽

Srinath Sundararajan

Keyword(s):

Liver Injury ◽

Liver Function ◽

Combination Therapy ◽

Hepatic Injury ◽

Mek Inhibitor ◽

New Combination ◽

Normal Range ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

First Case

Encorafenib/binimetinib is a new combination BRAF/MEK inhibitor used in the treatment of advanced or metastatic BRAFV600-mutant melanoma. Though generally tolerated well, mild to moderate aminotransferase elevations are common. However, significant liver injury has not been demonstrated in the literature. Here, we report the first case of severe hepatic injury associated with encorafenib/binimetinib in a 58-year-old gentleman requiring admission and extensive workup. He was successfully treated by withdrawing the combination therapy, and liver function returned to normal range.

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Gut microbiota and drug-induced liver injury

Chinese Medical Journal ◽

10.1097/cm9.0000000000000651 ◽

2020 ◽

Vol 133 (4) ◽

pp. 494-495

Author(s):

Meng-Wei Niu ◽

Peng Chen

Keyword(s):

Liver Injury ◽

Gut Microbiota ◽

Drug Induced ◽

Drug Induced Liver Injury

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Crocus sativus L. Extract Containing Polyphenols Modulates Oxidative Stress and Inflammatory Response against Anti-Tuberculosis Drugs-Induced Liver Injury

Plants ◽

10.3390/plants9020167 ◽

2020 ◽

Vol 9 (2) ◽

pp. 167 ◽

Cited By ~ 4

Author(s):

Adil Farooq Wali ◽

Jayachithra Ramakrishna Pillai ◽

Yusra Al Dhaheri ◽

Muneeb U. Rehman ◽

Ambreen Shoaib ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Inflammatory Response ◽

Hepatic Injury ◽

Standard Dose ◽

Crocus Sativus ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Response Status ◽

Crocus Sativus L

The purpose of this study is to analyze the polyphenolic rich extract of Crocus sativus L. petals (CSP) in modulating liver oxidative stress and inflammatory response status against rifampicin isoniazid (INH-RIF) drug-induced liver injury. The INH-RIF was administered for 14 days with varying doses in Wistar rats, while silymarin was administered as standard dose. We report the defensive impacts of CSP against INH-RIF induced liver oxidative stress and proinflammatory cytokine. The CSP treatment at both doses significantly controlled all modulating biochemical hepatic injury indicators and resulted in the attenuation of arbitral INH-RIF damage. The components present in CSP identified by LC–ESI-Q-TOF–MS were found to be flavonoids and fatty acids. It can be inferred that CSP possesses a hepatoprotective capacity against INH-RIF-mediated hepatic injury, which may prove to be a medically beneficial natural product for the management of drug-induced liver injury.

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Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Frontiers in Pharmacology ◽

10.3389/fphar.2021.790108 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ling Ye ◽

Zeying Feng ◽

Longjian Huang ◽

Chengjun Guo ◽

Xiong Wu ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Causality Assessment ◽

Sodium Succinate ◽

Assessment Method ◽

Drug Combinations ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Methylprednisolone Sodium Succinate ◽

Enzyme Metabolism

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China.Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI.Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%).Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

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A Severe Case of Drug-Induced Liver Injury after Gemcitabine Administration: A Highly Probable Causality Grading as Assessed by the Updated RUCAM Diagnostic Scoring System

Case Reports in Hepatology ◽

10.1155/2020/8812983 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Ilenia Mascherona ◽

Caterina Maggioli ◽

Maira Biggiogero ◽

Oreste Mora ◽

Lucia Marelli

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Clinical Presentation ◽

Acute Liver Injury ◽

Severe Case ◽

Suspected Drug ◽

Serum Enzyme ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Clinically Significant

Gemcitabine is an antineoplastic drug used in several forms of advanced pancreatic, lung, breast, ovarian, and bladder cancer. Common side effects include bone marrow suppression, fatigue, diarrhea, nausea, gastrointestinal upset, rash, alopecia, and stomatitis. Transient serum enzyme elevations could be observed during therapy, but clinically significant acute liver injury has been rarely associated with its use. Few cases of acute liver injury have been reported in the literature. We reported the clinical case of a 73--year-old man who developed clinically significant acute hepatic injury after using gemcitabine. Possible causes, clinical presentation, and treatments are discussed. According to the updated RUCAM score, the case was rated 10 points and became a suspected drug-induced liver injury. Moreover, on the liver biopsy, there were histological findings of mild-to-moderate portal hepatitis, eosinophilia, bile duct injury, and mild perisinusoidal fibrosis, suggesting drug damage.

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Weaning Mice and Adult Mice Exhibit Differential Carbon Tetrachloride-Induced Acute Hepatotoxicity

Antioxidants ◽

10.3390/antiox9030201 ◽

2020 ◽

Vol 9 (3) ◽

pp. 201 ◽

Cited By ~ 1

Author(s):

Tae Bin Jeong ◽

Doyoung Kwon ◽

Seung Won Son ◽

Sou Hyun Kim ◽

Yun-Hee Lee ◽

...

Keyword(s):

Liver Injury ◽

Liver Damage ◽

Drug Induced ◽

Glutamate Cysteine Ligase ◽

Stress Indicators ◽

Drug Induced Liver Injury ◽

Adult Mice ◽

Cellular Events ◽

Cyp 2E1 ◽

Old Adult

Age is a risk factor for drug-induced liver injury (DILI). However, there is a limited understanding of pediatric DILI. Here, 2-week-old weaning and 8-week-old adult male ICR mice were intraperitoneally injected with CCl4 (0.1 mmol/kg equal to 15.4 mg/kg) to comparatively evaluate the time-dependent liver damage and cellular events. CCl4 significantly enhanced the serum alanine aminotransferase/aspartate aminotransferase levels and hepatic centrilobular necrosis in the weaning mice, whereas it induced mild liver injury in the adult mice. CCl4-treated weaning mice exhibited higher hepatic levels of pro-apoptotic proteins (Bax, cleaved caspase-3, -7, and -9), activated MAPKs (p-JNK and p-Erk), and endoplasmic reticulum stress indicators (ATF6 and CHOP) and lower hepatic anti-apoptotic Bcl-2 levels than the adult mice. The weaning mice exhibited enhanced basal hepatic glutathione (GSH) levels due to high glutamate cysteine ligase (GCL) and low anti-cysteine dioxygenase (CDO) enzyme levels. However, CCl4 markedly reduced the hepatic GSH levels only in the weaning mice. Furthermore, higher hepatic levels of oxidative stress-induced malondialdehyde, 4-hydroxynonenal, nitrotyrosine-protein adducts, and oxidized proteins were observed in CCl4-treated weaning mice than in CCl4-treated adult mice. The enhanced levels of hepatic cytochrome P450 (CYP) 2E1 and CYP3A, and decreased hepatic GSH S-transferase (GST)-π and GSH reductase (GR) levels in the weaning mice may contribute to their enhanced susceptibility to liver damage.

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Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3320325 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yonela Ntamo ◽

Khanyisani Ziqubu ◽

Nireshni Chellan ◽

Bongani B. Nkambule ◽

Tawanda M. Nyambuya ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Hepatic Injury ◽

Clinical Evidence ◽

Antioxidant Properties ◽

Pathological Feature ◽

Protective Effects ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Acetyl Cysteine

Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.

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Leberschaden unter oraler Antikoagulation, Statin- und ACE-Hemmertherapie

Praxis ◽

10.1024/1661-8157/a000298 ◽

2010 ◽

Vol 99 (21) ◽

pp. 1259-1265 ◽

Cited By ~ 2

Author(s):

Bruggisser ◽

Terraciano ◽

Rätz Bravo ◽

Haschke

Keyword(s):

Liver Injury ◽

Wird Eine ◽

Drug Induced ◽

Drug Induced Liver Injury

Ein 71-jähriger Patient stellt sich mit Epistaxis und ikterischen Skleren auf der Notfallstation vor. Der Patient steht unter einer Therapie mit Phenprocoumon, Atorvastatin und Perindopril. Anamnestisch besteht ein langjähriger Alkoholabusus. Laborchemisch werden massiv erhöhte Leberwerte (ALAT, Bilirubin) gesehen. Der INR ist unter oraler Antikoagulation und bei akuter Leberinsuffizienz >12. Die weiterführenden Abklärungen schliessen eine Virushepatitis und eine Autoimmunhepatitis aus. Nachdem eine Leberbiopsie durchgeführt werden kann, wird eine medikamentös-toxische Hepatitis, ausgelöst durch die Komedikation von Atorvastatin, Phenprocoumon und Perindopril bei durch Alkohol bereits vorgeschädigter Leber diagnostiziert. Epidemiologie, Pathophysiologie und Klink der medikamentös induzierten Leberschäden (drug induced liver injury, DILI), speziell von Coumarinen, Statinen und ACE-Hemmern werden im Anschluss an den Fallbericht diskutiert.

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