Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but ...also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen species-mediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage.
Display omitted
•Mitochondrial DNA (mtDNA) encodes for proteins involved in oxidative phosphorylation.•Drugs can induce drug-induced liver injury (DILI) by altering mtDNA homeostasis.•Several drugs can severely reduce mtDNA levels by impairing mtDNA replication.•Drug-induced decreased mtDNA levels can also be secondary to oxidative stress.•Some drugs, mainly antibiotics, can impair mtDNA translation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies ...since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.
Full text
Available for:
FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The worldwide epidemic of obesity and insulin resistance favors nonalcoholic fatty liver disease (NAFLD). Insulin resistance (IR) in the adipose tissue increases lipolysis and the entry of ...nonesterified fatty acids (NEFAs) in the liver, whereas IR‐associated hyperinsulinemia promotes hepatic de novo lipogenesis. However, several hormonal and metabolic adaptations are set up in order to restrain hepatic fat accumulation, such as increased mitochondrial fatty acid oxidation (mtFAO). Unfortunately, these adaptations are usually not sufficient to reduce fat accumulation in liver. Furthermore, enhanced mtFAO without concomitant up‐regulation of the mitochondrial respiratory chain (MRC) activity induces reactive oxygen species (ROS) overproduction within different MRC components upstream of cytochrome c oxidase. This event seems to play a significant role in the initiation of oxidative stress and subsequent development of nonalcoholic steatohepatitis (NASH) in some individuals. Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. (Hepatology 2013;58:1497–1507)
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through ...cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mitochondrial fatty acid oxidation (mtFAO) is a key metabolic pathway required for energy production in the liver, in particular during periods of fasting. One major consequence of drug-induced ...impairment of mtFAO is hepatic steatosis, which is characterized by an accumulation of triglycerides and other lipid species, such as acyl-carnitines. Actually, the severity of this liver lesion is dependent on the residual mitochondrial β-oxidation flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is a benign lesion in the short term. Because some drugs can induce both microvesicular and macrovacuolar steatosis, it is surmised that severe mitochondrial dysfunction could be favored in some patients by non-genetic factors (e.g., high doses and polymedication), or genetic predispositions involving genes that encode proteins playing directly or indirectly a role in the mtFAO pathway. Example of drugs inducing steatosis include acetaminophen (APAP), amiodarone, ibuprofen, linezolid, nucleoside reverse transcriptase inhibitors, such as stavudine and didanosine, perhexiline, tamoxifen, tetracyclines, troglitazone and valproic acid. Because several previous articles reviewed in depth the mechanism(s) whereby most of these drugs are able to inhibit mtFAO and induce steatosis, the present review is rather focused on APAP, linezolid and troglitazone. These steatogenic drugs are indeed rarely discussed in the literature as regards their ability to impair mtFAO.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and ...hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed ...and over the counter drugs, DILI has become a major health issue for which there is a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause of ALF because of its extensive worldwide use as an analgesic. Despite intensive efforts utilising current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful discoveries by detailing the requirements for more realistic human-based systems to assess hepatotoxicity and guide future drug safety testing. We present novel insights and discuss major players in APAP pathophysiology, and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Fatty liver diseases can result from common metabolic diseases, as well as from xenobiotic exposure and excessive alcohol use, all of which have been shown to exert toxic effects on hepatic ...mitochondrial functionality and dynamics. Invasive or complex methodology limits large-scale investigations of mitochondria in human livers. Nevertheless, abnormal mitochondrial function, such as impaired fatty acid oxidation and oxidative phosphorylation, drives oxidative stress and has been identified as an important feature of human steatohepatitis. On the other hand, hepatic mitochondria can be flexible and adapt to the ambient metabolic condition to prevent triglyceride and lipotoxin accumulation in obesity. Experience from studies on xenobiotics has provided important insights into the regulation of hepatic mitochondria. Increasing awareness of the joint presence of metabolic disease-related (lipotoxic) and alcohol-related liver diseases further highlights the need to better understand their mutual interaction and potentiation in disease progression. Recent clinical studies have assessed the effects of diets or bariatric surgery on hepatic mitochondria, which are also evolving as an interesting therapeutic target in non-alcoholic fatty liver disease. This review summarises the current knowledge on hepatic mitochondria with a focus on fatty liver diseases linked to obesity, type 2 diabetes and xenobiotics.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although acetaminophen (APAP) is usually considered as a safe drug, this painkiller can lead to acute liver failure after overdoses. Moreover, there is evidence that the maximum recommended dosage ...can induce hepatic cytolysis in some individuals. Several predisposing factors appear to enhance the risk and severity of APAP‐induced liver injury including chronic alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions linked to obesity. In contrast, obesity by itself does not seem to be associated with a higher risk of APAP‐induced liver injury. Since 1987, seven studies dealt with APAP‐induced hepatotoxicity in rodent models of NAFLD and five of them found that this liver disease was associated with higher APAP toxicity. Unfortunately, these studies did not unequivocally established the mechanism(s) whereby NAFLD could favour APAP hepatotoxicity, although some investigations suggested that pre‐existent induction of hepatic cytochrome P450 2E1 (CYP2E1) could play a significant role by increasing the generation of N‐acetyl‐p‐benzoquinone imine (NAPQI), the toxic metabolite of APAP. Moreover, pre‐existent mitochondrial dysfunction associated with NAFLD could also be involved. In contrast, some investigations suggested that factors that could reduce the risk and severity of APAP hepatotoxicity in obesity and NAFLD include higher hepatic APAP glucuronidation, reduced CYP3A4 activity and increased volume of body distribution. Thus, the occurrence and the outcome of APAP‐induced liver injury in an obese individual with NAFLD might depend on a delicate balance between metabolic factors that can be protective and others that favour large hepatic levels of NAPQI.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. ...Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.
PDF
