Toxicity of some broad-spectrum antibacterials in normal rat liver: the role of mitochondrial membrane permeability transition pore

Oyebode, Olubukola T.; Adebiyi, Oluwaseun R.; Olorunsogo, Olufunso O.

doi:10.1080/15376516.2018.1528651

Cited by 13 publications

(10 citation statements)

References 28 publications

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“…46 In a case treated with cefepime, it was suggested that liver biochemistry showed elevation in the concentration of serum total bilirubin, ALT and AST. 40,47,48 In our work, hepatocellular necrosis was observed in liver cells of rats treated with cefepime, thus we agree with the point of view which attributes the increase of liver enzymes to the necrosis and alternation of membrane permeability of hepatocytes. In the current study, lipid vacuolations were observed in the hepatocytes of cefepime treated rats, such phenomenon was supported by the findings which suggested that cefepime interferes with the correlation of RNA with ribosomes, leading to lacking of protein building information which is a reason for the depletion in the synthesis of lipid acceptor protein in the hepatocytes, leading to inability of triglycerides to leave the hepatocytes resulting in accumulation of lipid inside the hepatocytes.…”

Section: Discussionsupporting

confidence: 91%

Vitamin C Ameliorates the Cefepime-Induced Changes of Liver Enzymes, Histopathology and Proinflammatory Cytokines in Male Albino Rats

Ahmad

Muaz

Abdein

et al. 2022

Int J Life Sci Pharm Res

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Section: Discussionsupporting

confidence: 91%

Vitamin C Ameliorates the Cefepime-Induced Changes of Liver Enzymes, Histopathology and Proinflammatory Cytokines in Male Albino Rats

Ahmad

Muaz

Abdein

et al. 2022

Int J Life Sci Pharm Res

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“…For example, it was shown that rotenone and several azoles induce mitochondrial toxicity through inhibition of the electron transport chain . Recently, it was shown that amoxicillin/clanvulanate and ciprofloxacin induce mitochondrial toxicity via the opening of the mitochondrial membrane permeability transition pore located in the outer membrane . Both findings highlight the association of the inhibition of certain mitochondrial proteins with mitochondrial toxicity.…”

Section: Resultsmentioning

confidence: 99%

Using Machine Learning Methods and Structural Alerts for Prediction of Mitochondrial Toxicity

Hemmerich

Troger

Füzi

et al. 2020

Molecular Informatics

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Over the last few years more and more organ and idiosyncratic toxicities were linked to mitochondrial toxicity. Despite well-established assays, such as the seahorse and Glucose/Galactose assay, an in silico approach to mitochondrial toxicity is still feasible, particularly when it comes to the assessment of large compound libraries. Therefore, in silico approaches could be very beneficial to indicate hazards early in the drug development pipeline. By combining multiple endpoints, we derived the largest so far published dataset on mitochondrial toxicity. A thorough data analysis shows that molecules causing mitochondrial toxicity can be distinguished by physicochemical properties. Finally, the combination of machine learning and structural alerts highlights the suitability for in silico risk assessment of mitochondrial toxicity.

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“…On the other hand, these proteins may play an important role in mitochondrial damage caused by compounds. Such as 3B96 is a homodimer related to the mitochondrial membrane and 4FDH can regulate electrolyte balance, and the out-of-balance of mitochondrial membrane potential is one of the mechanisms of DILI ( Jaeschke et al, 2012 ; Oyebode et al, 2019 ); 5G5J is related to the regulation of electron transport chain, and the inhibition of 5G5J activity induces mitochondrial toxicity and thus leads to DILI ( Chance and Hollunger, 1963 ; Hemmerich et al, 2020 ); 6G2M can regulate the levels of dTMP and dump to prevent excessive mutagenic dUTP from hindering the synthesis of mitochondrial DNA, and 5FS8 is an apoptosis-inducing factor. According to the previous study ( Jaeschke et al, 2012 ), apoptosis-inducing factors cause DNA damage in the nucleus and then trigger cell death.…”

Section: Discussionmentioning

confidence: 99%

Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury

et al. 2022

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Background and Aim: More than half of the small-molecule kinase inhibitors (KIs) induced liver injury clinically. Meanwhile, studies have shown a close relationship between mitochondrial damage and drug-induced liver injury (DILI). We aimed to study KIs and the binding between drugs and mitochondrial proteins to find factors related to DILI occurrence.Methods: A total of 1,223 oral FDA-approved drugs were collected and analyzed, including 44 KIs. Fisher’s exact test was used to analyze DILI potential and risk of different factors. A total of 187 human mitochondrial proteins were further collected, and high-throughput molecular docking was performed between human mitochondrial proteins and drugs in the data set. The molecular dynamics simulation was used to optimize and evaluate the dynamic binding behavior of the selected mitochondrial protein/KI complexes.Results: The possibility of KIs to produce DILI is much higher than that of other types (OR = 46.89, p = 9.28E-13). A few DILI risk factors were identified, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) ≥ 100 mg/day, the octanol–water partition coefficient (LogP) ≥ 3, and the degree of liver metabolism (LM) more than 50%. Drugs that met this combination of rules were found to have a higher DILI risk than controls (OR = 8.28, p = 4.82E-05) and were more likely to cause severe DILI (OR = 8.26, p = 5.06E-04). The docking results showed that KIs had a significant higher affinity with human mitochondrial proteins (p = 4.19E-11) than other drug types. Furthermore, the five proteins with the lowest docking score were selected for molecular dynamics simulation, and the smallest fluctuation of the backbone RMSD curve was found in the protein 5FS8/KI complexes, which indicated the best stability of the protein 5FS8 bound to KIs.Conclusions: KIs were found to have the highest odds ratio of causing DILI. MW was significantly related to the production of DILI, and the average docking scores of KI drugs were found to be significantly different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, and specific binding sites were analyzed. The optimization of molecular docking results by molecular dynamics simulation may contribute to further studying the mechanism of DILI.

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Toxicity of some broad-spectrum antibacterials in normal rat liver: the role of mitochondrial membrane permeability transition pore

Cited by 13 publications

References 28 publications

Vitamin C Ameliorates the Cefepime-Induced Changes of Liver Enzymes, Histopathology and Proinflammatory Cytokines in Male Albino Rats

Vitamin C Ameliorates the Cefepime-Induced Changes of Liver Enzymes, Histopathology and Proinflammatory Cytokines in Male Albino Rats

Using Machine Learning Methods and Structural Alerts for Prediction of Mitochondrial Toxicity

Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury

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