scholarly journals BML-257, a small molecule that protects against drug induced liver injury in zebrafish

2022 ◽  
Author(s):  
Urmila Jagtap ◽  
Sandeep Basu ◽  
Lavanya Lokhande ◽  
Nikhil Bharti ◽  
Chetana Sachidanandan

The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug induced liver injury (DILI) would be valuable in such situations. We used hepatocyte-specific expression of bacterial nitroreductase in zebrafish to cause temporally controlled liver damage. This transgenic line was used to run a whole organism based chemical screen in zebrafish larvae. In this screen we identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 also showed remarkable protective action in two independent toxicological models of liver injury caused by acetaminophen and Isoniazid. This suggests that BML-257 may have the potential to protect against multiple kinds of drug induced liver injury.

Author(s):  
J. Neuberger

Case History—A 22 yr old man, being treated for pulmonary tuberculosis, now presenting with confusion and jaundice. Drug-induced liver injury (DILI) is relatively uncommon but can very rarely be fatal. Almost all patterns of liver disease can be induced by drugs, and some drugs may be associated with more than one type of reaction. Some cases of DILI have a genetic component. Most cases present with jaundice and/or hepatitis....


2018 ◽  
Vol 1 (4) ◽  
pp. 105
Author(s):  
Donglin Zhu ◽  
Yun Xi ◽  
Jieming Dong ◽  
Fanhua Huang ◽  
Changzhi Xu ◽  
...  

 Objective: To investigate the relationship between cytochrome P450 E1 (CYP2E1) gene polymorphisms and susceptibility to anti-tuberculosis drug-induced liver damage (ATDLI) in tuberculosis patients in the Chinese Han nationality. Methods: A retrospective analysis was performed on 360 patients with tuberculosis who had liver damage after tuberculosis treatment (case group) and 360 patients with tuberculosis who did not develop liver injury after treatment (control group). MassARRAY were used to detect CYP2E1 gene polymorphisms. Results: In a total of 8 tagged SNP loci selected, the rs8192773 locus failed to pass the test, and therefore, it is not included in subsequent analysis. At the remaining seven SNP sites, the difference in alleles was not statistically significant between the case group and the control group, suggesting that these sites may not be related to liver damage caused by anti-tuberculosis drugs. Three monomer domains were found in the seven tags SNP loci mentioned above. However, it was found that these haplotypes are not closely related to anti-tuberculosis drug-induced liver damage. Conclusion: The CYP2E1 gene polymorphism in the Chinese Han nationality is not related to the occurrence of anti-tuberculosis drug-induced liver injury.


GYNECOLOGY ◽  
2018 ◽  
Vol 20 (6) ◽  
pp. 4-7
Author(s):  
A L Tikhomirov

Uterine fibroids are the most common pelvic tumor formation in women and the most common indication for hysterectomy. The effectiveness of long-term intermittent use of ulipristal acetate (UA) in patients with uterine myoma has been proven earlier. In May 2018, the ability of UA to cause a drug-induced liver injury (drug-induced liver injury, DILI) was disproved, and the European Commission approved a positive decision. According to the conclusion Expertise of the Pharmacovigilance Risk Assessment Committee (Pharmacovigilance Risk Assessment Committee - PRAC) the benefit/risk ratio remains favorable. Published recommendations are aimed at reducing the risk of liver damage. UA remains the 1st line of treatment for most myomas.


2018 ◽  
Vol 12 (3) ◽  
pp. 180-189 ◽  
Author(s):  
Maria Giovanna Minissale ◽  
Maurizio Soresi ◽  
Massimo Galia ◽  
Francesco Agnello ◽  
Lydia Giannitrapani ◽  
...  

Drug-induced liver injury (DILI) is often a trial even to expert clinicians, because sometimes diagnosis is not easy to be made. Guidelines of the American College of Gastroenterology (ACG) yielded in 2014, help to better understand the problem. The diagnosis of DILI is made through a detailed evaluation of clinical, serological, radiological and histological aspects. Biochemical data include liver function tests that allow to assess the pattern of damage, such as hepatocellular, cholestatic and mixed liver injury; serological data include testing for major and possibly minor hepatotropic viruses, non-organ specific autoantibodies. Clinical scenario might include jaundice, nausea, vomiting and extra-hepatic manifestations such as fever, pruritus, rash and eosinophilia. Investigation of the potential culprit drugs should involve firstly the temporal relationship between intake of the medication and onset of symptoms, thus the improvement after drug withdrawal. Overall, to complete the diagnostic evaluation, an abdominal ultrasound can be performed, as well as measurement of liver stiffness by transient elastography, and finally liver biopsy, which still represents the most accurate method to definitely assess liver damage. Sometimes, in such cases, computed tomography scan and magnetic resonance could help in the diagnosis of cases presenting with focal lesions of the liver, with cholestatic-like disease or vascular alterations, such as veno-occlusive disease. DILI diagnostic criteria help clinicians thinking of liver injury induced by drug, excluding other causes of liver disease. According to severity of liver damage and type of drug, it is possible to carefully predict the patient’s outcome.


2006 ◽  
Vol 44 ◽  
pp. S247
Author(s):  
R.J. Andrade ◽  
M.I. Lucena ◽  
K. Pachkoria ◽  
Y. Borraz ◽  
N. Kaplowitz ◽  
...  

2020 ◽  
Vol 10 (3) ◽  
pp. 244-248
Author(s):  
Mehr Fatima ◽  
Syed Zaidi

Drug induced liver injury is one of the main factor of liver failure and acute liver damage world wide with high incidence in western countries. Liver injury can be intrinsic (dose dependant) or idiosyncratic (dose independent). However idiosyncratic type is considered to be mainly responsible for drug induced liver damage. Binding of reactive metabolites of drugs to tissue proteins and oxidative stress is the possible cellular mechanism involved in this process. Moreover, some antibiotics, anti-epileptics, nonsteroidal anti-inflammatory drugs etc are more likely to induce liver damage in high risks groups that includes females, elderly and obese people. HLA halotype and variation in protein expression also plays an important role in this context. Various studies are available regarding clinical features, histopathological features, diagnosis and management related to antibiotics and acetaminophen induced liver damage. N acetylcysteine is commonly available antidote for drug induced hepatic damage. Role of other pharmacological agents as an antidote requires further studies. However, liver transplantation should be considered with drug induced lethal liver failure


Author(s):  
R. Mark Beattie ◽  
Anil Dhawan ◽  
John W.L. Puntis

Epidemiology 374Pathophysiology 374Herbal drugs and alternative medicines 377Risk factors 377Clinical features 378Investigation 379Management 380Drug induced liver injury (DILI) is a variable and complex diagnosis of exclusion, as it can present in different ways. Because of the liver's central role in drug metabolism, most prescribed drugs can cause liver injury. Liver damage can occur through drugs in a predictable, intrinsic dose-related way or in a unpredictable, idiosyncratic dose-unrelated fashion....


2020 ◽  
Vol 18 (3) ◽  
pp. 155-164
Author(s):  
Diana Muraviova ◽  
◽  
Yuliia Kharchenko ◽  
Kateryna Pierzynowska ◽  
Stefan Pierzynowski ◽  
...  

Introduction. Recently, more attention is being paid to the drug-induced liver injury (DILI) as a consequence of the tuberculos is treatment and the need for new medicine is emphasized. The use of isoniazid and rifampicin has a potentiating effect, which increases the risk of substancial liver damage. In turn, systemic accumulation of toxic metabolites leads to negative changes in various organs, including the brain. It causes an imbalance in biochemical and neurophysiological processes in the brain, ultimately giving the onset to the development of hepatic encephalopathy. Aim. The effects of rifampicin and isoniazid on the central nervous system have not been studied before and we aimed to evaluate the impact these two substances have on the neuronal cell adhesion molecules (NCAM) distribution and animal behavior in the rat model of DILI. Material and methods. The 24 male Wistar rats, weighing 180-220 g were used for the experiment and divided to the groups (n=6): 1 – control; 2 – rats with experimental DILI; 3 – rats with DILI plus the intravenous infusion of S-adenosyl-L-methionine at a dose of 35 mg/kg; 4 – rats with DILI plus a fixed combination of ipidacrine hydrochloride at a dose 1 mg/kg body weight and phenibut at a dose 60 mg/kg body weight daily for the last 14 days of the experiment. All experimental procedures were carried out in the accordance with the principles outlined in the current Guide to the Care and Use of Experimental Animals. The locomotor and research activities were studied in the open field test. The activity of aspartate aminotransferase (AST, ЕС 2.6.1.1) and alanine aminotransferase (ALT, ЕС 2.6.1.2) in the serum of rats were tested to confirm the liver damage. The quantitative analyses of soluble and membrane forms of NCAM were performed with ELISA. The ANOVA followed by a Tukey post-hoc test was used to assess statistical differences between groups. Results. Our investigation in the open field test revealed a significant decrease in the locomotor and research activity of rats after 28 days of rifampicin and isoniazid administration. The recovery of investigated parameters was observed in groups of animals treated with ademetionine (AD group) or combination of ipidacrine and phenibut (IP/PB group). We also observed that changes in rats’ behavior were consistent with alterations of the NCAM levels in the thalamus and hippocampus. Thus, the level of membrane NCAM was significantly decreased under DILI in both investigated brain regions (thalamus and hippocampus), while both AD and IP/PB treatments restored membrane NCAM levels towards those observed in the control group at least in the hippocampus. Conclusion. Obtained data suggests that both ademetionine and combinated drug containing ipidacrine and phenibut possesses neuroprotective properties and could prevent the decline in synaptic plasticity under antitubercular therapy.


Antioxidants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 201 ◽  
Author(s):  
Tae Bin Jeong ◽  
Doyoung Kwon ◽  
Seung Won Son ◽  
Sou Hyun Kim ◽  
Yun-Hee Lee ◽  
...  

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.


2021 ◽  
Author(s):  
Huiqun Dong ◽  
Jia You ◽  
Yu Zhao ◽  
Danhua Zheng ◽  
Yi Zhong ◽  
...  

BACKGROUND Preventing Drug-induced liver injury (DILI) in advance is an important task to improve drug safety and protect patient health. It was reported that more than half of small-molecule kinase inhibitors (KIs) induced DILI clinically. Meanwhile, numerous studies have shown a close relationship between mitochondrial damage and the generation of DILI. OBJECTIVE We aimed to focused on KIs to find factors related to DILI occurrence and study the binding potential between the whole class of drugs and mitochondrial proteins and further analysis of the key proteins in silico. METHODS 1,223 drugs approved by the Food and Drug Administration (FDA) were collected and analyzed, including 44 KIs. Fisher exact test was used to analyze DILI potential and risk of different factors. 187 human mitochondrial proteins were further collected and high-throughput molecular docking was performed between them and drugs in the data set. RESULTS Be The possibility of KIs to produce DILI is much higher than other types (odds ratio [OR] = 46.89, 95% CI [confidence interval] = 6.44 ~ 341.63, P = 9.28E-13). A few DILI risk factors were found, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) greater than or equal to 100mg/day, the octanol-water partition coefficient (LogP) greater than or equal to 3, and the degree of liver metabolism (LM) more than 50% (‘400 ≤ MW < 600 & LogP ≥ 3 & DDD ≥ 100 & LM ≥ 50%’). Drugs that met this combination of rules were found to have higher DILI risk than controls (OR = 8.28, 95% CI = 2.46 ~ 27.82, P = 4.82E-05, PPV [positive predictive value] = 88%) and were more likely to cause severe DILI (OR = 8.26, 95% CI = 2.25 ~ 30.26, P = 5.06E-04). The docking results showed that KIs had significant higher affinity with human mitochondrial proteins (P = 4.19E-11), which may be an implication for higher DILI potential. CONCLUSIONS KIs were found to have the highest odds ratio of causing DILI. Some characteristics of KIs were significantly related to the production of DILI. And the average docking scores of KIs drugs were found to be significant different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, which may help with the study of the mechanism of DILI. CLINICALTRIAL Not applicable.


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