Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results

Doß, Sandra; Potschka, H.; Mitzner, Steffen; Sauer, Martin

doi:10.1155/2017/9658018

Cited by 15 publications

(21 citation statements)

References 67 publications

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“…In vitro studies have shown that some antimycotics like fluconazole and anidulafungin have got a dose-dependent effect on albumin synthesis. High concentrations of these drugs can cause cellular necrosis [15]. Our patient with complex pathophysiological changes due to sepsis showed a significant decrease in serum albumin.…”

Section: Discussionmentioning

confidence: 61%

“…Maintaining a regular dose of 50 mg/d may lead to toxic blood concentrations which may result in drug-induced liver injury (DILI) [14]. Vitality, viability, and function of hepatocytes is remarkedly impaired in vitro, when echinocandins are overdosed [15]. e protein amount seems to matter, as 95% of caspofungin are bound to plasma proteins, especially albumin [16].…”

Section: Discussionmentioning

confidence: 99%

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Dosing of Antimycotic Treatment in Sepsis–Induced Liver Dysfunction by Functional Liver Testing with LiMAx®

Kirchner

Sibai

Schwier

et al. 2019

Case Reports in Critical Care

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Background. Sepsis-treatment is one of the major challenges in our time. Especially fungal infections play an important role in patient’s morbidity and mortality. In patients with septic shock, liver function is often significantly impaired and therefore also hepatic drug metabolism is altered. Case Presentation. We report about a 56-year-old man suffering from invasive fungal infection with multiorgan failure, after complicated medical history due to symptomatic infrarenal aortic aneurysm. On the first postoperative day, a CT scan was undertaken due to massive back pain showing renal infarction on both sides. As qualitative and quantitative renal function was impaired, hemodialysis was started immediately. Subsequently, the patient developed a compartment syndrome of the left leg and underwent fasciotomy. On admission day 7, the patient presented with hematochezia leading to colonoscopy. During this procedure, an ischemic colitis was observed. As conservative treatment failed, the patient underwent Hartmann’s procedure due to progredient ischemia followed by a worsening of the clinical status due to sepsis. The patient suffered from an invasive fungal infection with Candida spp. and Aspergillus spp. Systemic antifungal treatment was initiated. Although azoles are considered first-line treatment in these cases we chose the echinocandin caspofungin for its presumed lower impact on liver function compared to azoles like voriconazole or Amphothericin B. However, caspofungin is also metabolised in the liver and can cause hepatotoxic effects. Therefore we measured metabolic liver function capacity using LiMAx®and adapted the patient’s dose of caspofungin to the evaluated liver function capacity to achieve an effective and liver-protective level of the active drug. After complicated medical history with 15 weeks of hospital stay, the patient was discharged in general good condition. Conclusions. To our knowledge, this is the first report that relates antimycotic drug dosing to a functional liver test. We provide a new approach for sepsis treatment considering liver function capacity to optimize dosage of hepatically metabolised drugs with potential hepatotoxic effects.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Dosing of Antimycotic Treatment in Sepsis–Induced Liver Dysfunction by Functional Liver Testing with LiMAx®

Kirchner

Sibai

Schwier

et al. 2019

Case Reports in Critical Care

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“…Here we study the effect of albumin on HepG2/C3A hepatocellular carcinoma cell line, a contact inhibited subclone of the HepG2 cell line (Aden et al, 1979) that retains some physiological functions of normal hepatocytes (Kelly et al, 1992;Nibourg et al, 2012). The HepG2/C3A cells are used as a model cell line for studying parenchymal biosynthesis (Knowles, Howe & Aden, 1980;Zannis et al, 1981;Nibourg et al, 2012) and screening for cytotoxicity of drug compounds for side effects involving liver injury (Gaskell et al, 2016;Doß et al, 2017). The cell line has also been considered for testing clinical samples in screening for diseases (Sauer et al, 2012;Sauer et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Although similar studies have been previously performed on the HepG2 hepatocellular carcinoma parent clone demonstrating that albumin prevents proliferation (Nojiri & Joh, 2014;Bağırsakçı et al, 2017), experiments in this study were carried out on the HepG2/C3A subclone and were contradictory to these earlier findings. Since HepG2/C3A cell line is commonly used as a model for drug testing (Gaskell et al, 2016;Doß et al, 2017), it is justifiable to have a basic understanding of the effects of albumin on HepG2/C3A cells when testing albumin bound drugs. This primary approach offers a platform and a control method when studying the effects of drug bound albumin and pathologically modified albumin on cell proliferation as well as cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Albumin promotes proliferation of G1 arrested serum starved hepatocellular carcinoma cells

Ibrahim

Stange

Dominik

et al. 2020

PeerJ

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Albumin is the most abundant plasma protein and functions as a transport molecule that continuously interacts with various cell types. Because of these properties, albumin has been exploited by the pharmaceutical industry to improve drug delivery into target cells. The immediate effects of albumin on cells, however, require further understanding. The cell interacting properties and pharmaceutical applications of albumin incentivises continual research into the immediate effects of albumin on cells. The HepG2/C3A hepatocellular carcinoma cell line is used as a model for studying cancer pathology as well as liver biosynthesis and cellular responses to drugs. Here we investigated the direct effect of purified albumin on HepG2/C3A cell proliferation in the absence of serum, growth factors and other serum originating albumin bound molecules. We observed that the reduced cell counts in serum starved HepG2/C3A cultures were increased by the inclusion of albumin. Cell cycle analysis demonstrated that the percentage of cells in G1 phase during serum starvation was reduced from 86.4 ± 2.3% to 78.3 ± 3.2% by the inclusion of albumin whereas the percentage of cells in S phase was increased from 6.5 ± 1.5% to 14.3 ± 3.6%. A significant reduction in the cell cycle inhibitor protein, P21, accompanied the changes in the proportions of cell cycle phases upon treatment with albumin. We have also observed that the levels of dead cells determined by DNA fragmentation and membrane permeabilization caused by serum starvation (TUNEL: 16.6 ± 7.2%, ethidium bromide: 13.8 ± 4.8%) were not significantly altered by the inclusion of albumin (11.6 ± 10.2%, ethidium bromide: 16.9 ± 8.9%). Therefore, the increase in cell number was mainly caused by albumin promoting proliferation rather than protection against cell death. These primary findings demonstrate that albumin has immediate effects on HepG2/C3A hepatocellular carcinoma cells. These effects should be taken into consideration when studying the effects of albumin bound drugs or pathological ligands bound to albumin on HepG2/C3A cells.

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Section: Introductionmentioning

confidence: 99%

Peer Review #2 of "Albumin promotes proliferation of G1 arrested serum starved hepatocellular carcinoma cells (v0.1)"

2020

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Albumin is the most abundant plasma protein and functions as a transport molecule that continuously interacts with various cell types. Because of these properties, albumin has been exploited by the pharmaceutical industry to improve drug delivery into target cells. The immediate effects of albumin on cells however require further understanding. The cell interacting properties and pharmaceutical applications of albumin incentivises continual research into the immediate effects of albumin on cells. The HepG2/C3A hepatocellular carcinoma cell line is used as a model for studying cancer pathology as well as liver biosynthesis and cellular responses to drugs. Here we investigated the direct effect of purified albumin on HepG2/C3A cell proliferation in the absence of serum, growth factors and other serum originating albumin bound molecules. We observed that the reduced cell counts in serum starved HepG2/C3A cultures were increased by the inclusion of albumin. Cell cycle analysis demonstrated that the percentage of cells in G1 phase during serum starvation was reduced from 86.4±2.3 % to 78.3±3.2 % by the inclusion of albumin whereas the percentage of cells in S phase was increased from 6.5±1.5 % to 14.3±3.6 %. A significant reduction in the cell cycle inhibitor protein, P21, accompanied the changes in the proportions of cell cycle phases upon treatment with albumin. We have also observed that the levels of dead cells determined by DNA fragmentation and membrane permeabilization caused by serum starvation (TUNEL: 16.6 ± 7.2 %, ethidium bromide: 13.8±4.8 %) were not significantly altered by the inclusion of albumin (11.6 ± 10.2 %, ethidium bromide: 16.9 ± 8.9 %). Therefore, the increase in cell number was mainly caused by albumin promoting proliferation rather than protection against cell death. These primary findings demonstrate that albumin has immediate effects on HepG2/C3A hepatocellular carcinoma cells. These effects should be taken into consideration when studying the effects of albumin bound drugs or pathological ligands bound to albumin on HepG2/C3A cells.

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Hepatotoxicity of Antimycotics Used for Invasive Fungal Infections: In Vitro Results

Cited by 15 publications

References 67 publications

Dosing of Antimycotic Treatment in Sepsis–Induced Liver Dysfunction by Functional Liver Testing with LiMAx®

Dosing of Antimycotic Treatment in Sepsis–Induced Liver Dysfunction by Functional Liver Testing with LiMAx®

Albumin promotes proliferation of G1 arrested serum starved hepatocellular carcinoma cells

Peer Review #2 of "Albumin promotes proliferation of G1 arrested serum starved hepatocellular carcinoma cells (v0.1)"

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