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Nevirapine effects on hepatocytes. A & B: nevirapine-induced a heterogeneous pattern of damage in the liver where some hepatocytes appeared to have necrotic cytoplasm and degenerate mitochondria (DM) (see hepatocyte on the left) while others appeared mostly unaffected (hepatocyte on the right). C & D: cellular debris of necrotic cells (arrows) scattered around hepatocytes and in sinusoidal lumen (SL). L: lipid droplets; RBC: red blood cell.
Source publication
Nevirapine (NVP) therapy is associated with a high risk of serious liver injury and skin rash. Treatment of Brown Norway rats with NVP causes an immune-mediated skin rash. Even though NVP does not cause serious liver injury in wildtype animals, incubation of hepatocytes with NVP leads to the release of presumably danger-associated molecular pattern...
Contexts in source publication
Context 1
... tissue from the treated rats showed a hetero- geneous pattern of damage where some hepato- cytes appeared to have been affected by the drug and developed necrotic cytoplasm as well as degenerate mitochondria while others appeared unaffected ( Figure 1A & B). The damage in the affected hepatocytes varied in degrees of cellular degeneration to necrosis ( Figure 1B & C). The cytoplasm of some cells was granular and depleted ( Figure 1B). Debris from necrotic cells could be found around the hepatocytes ( Figure 1C). In some areas, the membrane of hepatocytes had severely deteriorated leading to cell contents enter- ing sinusoids ( Figure 1C & D, ...
Context 2
... tissue from the treated rats showed a hetero- geneous pattern of damage where some hepato- cytes appeared to have been affected by the drug and developed necrotic cytoplasm as well as degenerate mitochondria while others appeared unaffected ( Figure 1A & B). The damage in the affected hepatocytes varied in degrees of cellular degeneration to necrosis ( Figure 1B & C). The cytoplasm of some cells was granular and depleted ( Figure 1B). Debris from necrotic cells could be found around the hepatocytes ( Figure 1C). In some areas, the membrane of hepatocytes had severely deteriorated leading to cell contents enter- ing sinusoids ( Figure 1C & D, ...
Context 3
... tissue from the treated rats showed a hetero- geneous pattern of damage where some hepato- cytes appeared to have been affected by the drug and developed necrotic cytoplasm as well as degenerate mitochondria while others appeared unaffected ( Figure 1A & B). The damage in the affected hepatocytes varied in degrees of cellular degeneration to necrosis ( Figure 1B & C). The cytoplasm of some cells was granular and depleted ( Figure 1B). Debris from necrotic cells could be found around the hepatocytes ( Figure 1C). In some areas, the membrane of hepatocytes had severely deteriorated leading to cell contents enter- ing sinusoids ( Figure 1C & D, ...
Context 4
... tissue from the treated rats showed a hetero- geneous pattern of damage where some hepato- cytes appeared to have been affected by the drug and developed necrotic cytoplasm as well as degenerate mitochondria while others appeared unaffected ( Figure 1A & B). The damage in the affected hepatocytes varied in degrees of cellular degeneration to necrosis ( Figure 1B & C). The cytoplasm of some cells was granular and depleted ( Figure 1B). Debris from necrotic cells could be found around the hepatocytes ( Figure 1C). In some areas, the membrane of hepatocytes had severely deteriorated leading to cell contents enter- ing sinusoids ( Figure 1C & D, ...
Context 5
... tissue from the treated rats showed a hetero- geneous pattern of damage where some hepato- cytes appeared to have been affected by the drug and developed necrotic cytoplasm as well as degenerate mitochondria while others appeared unaffected ( Figure 1A & B). The damage in the affected hepatocytes varied in degrees of cellular degeneration to necrosis ( Figure 1B & C). The cytoplasm of some cells was granular and depleted ( Figure 1B). Debris from necrotic cells could be found around the hepatocytes ( Figure 1C). In some areas, the membrane of hepatocytes had severely deteriorated leading to cell contents enter- ing sinusoids ( Figure 1C & D, ...
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... lipid droplets were present in hepatocytes throughout the specimens (Figure 2A-D). Concentric whirls of smooth endoplasmic reticu- lum (SER) cisternae surrounded a number of fat droplets forming a structure that we termed lipid- SER (LSER) inclusions (Figure 2A & B). The size of the lipid droplets within the LSER inclusions averaged 0.85 μm (±0.54). Some of the large lipid droplets may have resulted from the fusion of several smaller droplets; an LSER inclusion may have more than 10 lipid droplets (Figure 2C & D). Some LSER inclusions appeared with degen- erate SER membranes inside them (Figures 1D and 2C & D, arrow heads). SER whorls were reduced or absent around LSER inclusions close to or within sinusoids ( Figures 1D and 2D, arrow ...
Citations
... Clinical studies suggest that alcohol, antiretroviral therapy and hepatotropic viruses (Hepatitis B and C) may be associated with liver disease among HIV-infected individuals [47]. While the mechanisms of hepatotoxicity by antiretroviral therapy [48,49] and hepatotropic viruses [50,51] have been extensively explored, the mechanisms explaining the role of alcohol in HIV-infection and pathogenesis of liver disease development has not received adequate attention despite the emerging burden of liver disease in HIV management [52]. In response, this study explored preclinical experimental designs to decipher ethanol-induced mechanisms in hepatocytes exposed to HIV. ...
Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (ABAGS+HIV). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1ADA and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte ABAGS+HIV engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH.
... Brown Norway rats treated with NVP (150 mg/kg/day for 8 weeks, through diet) showed a heterogeneous pattern of liver damage, by which some hepatocytes were affected by the drug and developed necrotic cytoplasm and mitochondrial degeneration, while others appeared to be unaffected. Hepatocyte injury was demonstrated by the presence of granular cytoplasm, abnormal lipid inclusions, prevalent destruction of mitochondrial inner membrane and lipid-smooth endoplasmic reticulum (LSER) inclusions, and liver biopsies from treated rats also displayed varying degrees of endothelial abnormalities [73]. Hepatocytes do not seem to further process LSERs, but rather to expel them into the blood stream, from where they can be picked up by lymph nodes and contribute to initiation of an immune response that leads to serious liver injury or skin rash. ...
... Hepatocytes do not seem to further process LSERs, but rather to expel them into the blood stream, from where they can be picked up by lymph nodes and contribute to initiation of an immune response that leads to serious liver injury or skin rash. In NVP-administered rats, the formation of LSER inclusions appears to be a mechanism of sequestration and evacuation of this NNRTI or its metabolites from hepatocytes abnormalities [73]. Although NVP causes an immune-mediated skin rash in Brown Norway rats, it does not cause significant hepatic necrosis as measured by serum ALT, presumably because the dominant immune response in the liver is immune tolerance. ...
Due to the improved effectiveness and safety of combined antiretroviral therapy, human immunodeficiency virus (HIV) infection has become a manageable, chronic condition rather than a mortal disease. However, HIV patients are at increased risk of experiencing non-AIDS-defining illnesses, with liver-related injury standing out as one of the leading causes of death among these patients. In addition to more HIV-specific processes, such as antiretroviral drug-related toxicity and direct injury to the liver by the virus itself, its pathogenesis is related to conditions that are also common in the general population, such as alcoholic and non-alcoholic fatty liver disease, viral hepatitis, and ageing. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of combined anti-HIV treatment due to their unique antiviral activity, high specificity, and acceptable toxicity. While first-generation NNRTIs (nevirapine and efavirenz) have been related largely to liver toxicity, those belonging to the second generation (etravirine, rilpivirine and doravirine) seem to be generally safe for the liver. Indeed, there is preclinical evidence of rilpivirine being hepatoprotective in different models of liver injury, independently of the presence of HIV. The present study aims to review the mechanisms by which currently available anti-HIV drugs belonging to the NNRTI family may participate in the development of liver disease.
... Aberrations in lipid homeostasis may also induce ER stress (Song and Malhi, 2019). Although, compared with proteins, changes to lipids have not been studied as extensively in the context of IDRs, this may be an interesting avenue to explore; for example, lipid-smooth ER inclusions were found in hepatocytes of brown Norway rats administered nevirapine (Sastry et al., 2018), which is also known to induce smooth ER hypertrophy (Sharma et al., 2012). ...
Idiosyncratic drug reactions (IDRs) range from relatively common, mild reactions to rarer, potentially life-threatening adverse effects that pose significant risks to both human health and successful drug discovery. Most frequently, IDRs target the liver, skin, and blood or bone marrow. Clinical data indicate that most IDRs are mediated by an adaptive immune response against drug-modified proteins, formed when chemically reactive species of a drug bind to self-proteins, making them appear foreign to the immune system. Although much emphasis has been placed on characterizing the clinical presentation of IDRs and noting implicated drugs, limited research has focused on the mechanisms preceding the manifestations of these severe responses. Therefore, we propose that to address the knowledge gap between drug administration and onset of a severe IDR, more research is required to understand IDR-initiating mechanisms; namely, the role of the innate immune response. In this review, we outline the immune processes involved from neoantigen formation to the result of the formation of the immunologic synapse and suggest that this framework be applied to IDR research. Using four drugs associated with severe IDRs as examples (amoxicillin, amodiaquine, clozapine, and nevirapine), we also summarize clinical and animal model data that are supportive of an early innate immune response. Finally, we discuss how understanding the early steps in innate immune activation in the development of an adaptive IDR will be fundamental in risk assessment during drug development. SIGNIFICANCE STATEMENT: Although there is some understanding that certain adaptive immune mechanisms are involved in the development of idiosyncratic drug reactions, the early phase of these immune responses remains largely uncharacterized. The presented framework refocuses the investigation of IDR pathogenesis from severe clinical manifestations to the initiating innate immune mechanisms that, in contrast, may be quite mild or clinically silent. A comprehensive understanding of these early influences on IDR onset is crucial for accurate risk prediction, IDR prevention, and therapeutic intervention.
... Previously, mitochondrial damage has been observed during in vivo rat and in vitro Hep G2 cell treatment with NVP. 48,49 The implications of the various changes observed in the protein abundances warrant further exploration. One example, FAST kinase domain-containing protein 5 (FASTKD5, which was significantly decreased in human primary hepatocytes treated with NVP and 12-D 3 NVP), has been previously demonstrated to be involved in noncanonical mitochondrial mRNA processing. ...
Cytochrome P450-dependent metabolism of the anti-HIV drug nevirapine (NVP) to 12-hydroxy-NVP (12-OHNVP) has been implicated in NVP toxicities. We investigated the impact of twelfth-position trideuteration (12-D3NVP) on hepatic metabolism of and response to NVP. Formation of 12-OHNVP decreased in human (10.6-fold) and mouse (4.6-fold) hepatocytes incubated with 10 µM of 12-D3NVP versus NVP. An observed kinetic isotope effect of 10.1 was measured in human liver microsomes. During mouse hepatocyte treatment (400 µM) with NVP or 12 D3NVP, cell death was reduced 30% with 12-D3NVP versus NVP, while glucuronidated and glutathione conjugated metabolites increased with 12-D3NVP versus NVP. Using mass spectrometry proteomics, changes in hepatocyte protein expression, including an increase in stress marker IGFBP-1, were observed with 12-D3NVP versus NVP. These results demonstrate that while deuteration can reduce P450 metabolite formation, impacts on phase II metabolism and hepatocyte protein expression should be considered when employing deuteration to reduce P450 metabolite-related hepatotoxicity.
