Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes

Berson, Alain; Beco, V. De; Lettéron, Philippe; Robin, Marie Anne; Moreau, C. Page; Kahwaji, Johny El; Verthier, Nicole; Feldmann, Gérard; Fromenty, Bernard; Pessayre, Dominique

doi:10.1016/s0016-5085(98)70590-6

Cited by 355 publications

(225 citation statements)

References 21 publications

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“…A plausible explanation is that fat stored in lipid droplets of hepatocytes may be oxidized by oxidation catalysts or reactive oxygen species. 6,31 Our immunoelectron microscopic observation, where oxPC immunoreactivity was seen at the rim of lipid droplets, is in accordance with this explanation. Another possibility is that oxPC localization in steatotic livers is the result of cellular uptake of oxLDL into macrophages/Kupffer cells and hepatocytes.…”

Section: Discussionsupporting

confidence: 87%

“…[4][5][6][7] A sophisticated 2-hit theory of the pathogenesis of NASH/NAFLD emphasizes oxidative stress as the most important factor that causes a "second hit." [4][5][6][7] As a consequence of oxidative tissue injury, many kinds of oxidation-related products, oxidatively modified lipids, proteins, and nucleotides, are generated. 27 Thus, these products can be used as markers of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…In their theory, oxidative stress is considered the most likely factor as the "second hit," a key event for disease progression. [4][5][6][7] Accumulating evidence suggests oxidative stress plays an etiopathogenic role in diseases of various organs/tissues. Atherosclerosis, which frequently occurs in association with metabolic disorders such as hyperlipidemia or diabetes, is one example where oxidative stress contributes to its pathogenic mechanism.…”

mentioning

confidence: 99%

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Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Ikura¹,

Ohsawa²,

Suekane³

et al. 2006

Hepatology

126

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Nonalcoholic steatohepatitis/nonalcoholic fatty liver disease is considered to be a hepatic manifestation of various metabolic disorders. However, its precise pathogenic mechanism is obscure. Oxidative stress and consequent lipid peroxidation seem to play a pivotal role in disease progression. In this study, we analyzed the localization of oxidized phosphatidylcholine (oxPC), a lipid peroxide that serves as a ligand for scavenger receptors, in livers of patients with this steatotic disorder. Specimens of nonalcoholic fatty liver disease (15 autopsy livers with simple steatosis and 32 biopsy livers with steatohepatitis) were examined via immunohistochemistry and immunoelectron microscopy using a specific antibody against oxPC. In addition, scavenger receptor expression, hepatocyte apoptosis, iron deposition, and inflammatory cell infiltration in the diseased livers were also assessed. Oxidized phosphatidylcholine was mainly localized to steatotic hepatocytes and some macrophages/Kupffer cells. A few degenerative or apoptotic hepatocytes were also positive for oxPC. Immunoelectron microscopy showed oxPC localized to cytoplasmic/intracytoplasmic membranes including lipid droplets. Steatotic livers showed enhanced expression of scavenger receptors. The number of oxPC cells was correlated with disease severity and the number of myeloperoxidasepositive neutrophils, but not with the degree of iron deposition. In conclusion, distinct localization of oxPC in liver tissues suggest that neutrophil myeloperoxidase-derived oxidative stress may be crucial in the formation of oxPC and the progression of steatotic liver disease. (HEPATOLOGY 2006;43:506-514.)

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Ikura¹,

Ohsawa²,

Suekane³

et al. 2006

Hepatology

126

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“…Studies using isolated hamster liver mitochondria showed that a concentration dependent decrease in mitochondrial membrane potential on treatment with AMD, without evidence of thiobarbituric acid-reactive substances formation, suggesting that AMD brings about its effect independent of lipid peroxidation in vitro [189]. Interestingly, however, while in vitro studies by the Pessayre group showed that exposure of isolated rat liver mitochondria to AMD resulted in increased mitochondrial ROS formation, use of ethane exhalation as an index of lipid peroxidation in vivo showed elevations by 24 hours after administration of AMD to rats [190]. Studies by the Pessayre laboratory have also found that AMD inhibited mitochondrial beta-oxidation of fatty acids and produced microvesicular steatosis of the liver in mice [191].…”

Section: Amiodarone Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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“…11) Microvesicular steatosis is identiˆed by the presence of multiple small lipid droplets in hepatic sections and appears to be secondary to mitochondrial injury (which results in impaired b-oxidation of fatty acids and impaired respiration leading to ATP depletion) and W or to decreased synthesis of lipoproteins by the liver. [12][13][14] Although early steatosis may be reversible, continued hepatotoxic injury may lead toˆbrosis and eventual cirrhosis. In patients with cirrhosis of the liver, it has been reported that urinary excretion of N 1 -methylnicotinamide (MNA), which is a main catabolic metabolite of NAD, twofold increase in comparison with normal subjects.…”

mentioning

confidence: 99%

Effects of Fatty Liver Induced by Niacin-free Diet with Orotic Acid on the Metabolism of Tryptophan to Niacin in Rats

Fukuwatari

Morikawa

Sugimoto

et al. 2002

Bioscience, Biotechnology, and Biochemistry

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Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes

Cited by 355 publications

References 21 publications

Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

Effects of Fatty Liver Induced by Niacin-free Diet with Orotic Acid on the Metabolism of Tryptophan to Niacin in Rats

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