Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity

Fromenty, Bernard; Pessayre, Dominique

doi:10.1016/0163-7258(95)00012-6

Cited by 602 publications

(534 citation statements)

References 428 publications

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“…The accumulation of lipids in the steatotic liver may have produced a severe impairment of mitochondrial beta-oxidation of fatty acids, and thus microvesicular steatosis as proposed by Fromenty and Pessayre (1995). Microvesicular steatosis has been reported in other pathologic conditions of ewes affecting mitochondrial metabolism, such as cobalt deficiency (Kennedy et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

“…Microvesicular steatosis has been reported in other pathologic conditions of ewes affecting mitochondrial metabolism, such as cobalt deficiency (Kennedy et al, 1997). Similarly, acute fatty liver during late pregnancy in humans is characterized by microvesicular steatosis (Fromenty and Pessayre, 1995;Burt, 2001). The mild steatotic changes observed in the liver of ewes that recovered from pregnancy toxemia, suggests that fatty liver with microvesicular steatosis can be reversed if treated.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Histological changes of the liver and metabolic correlates in ewes with pregnancy toxemia

Cal

Borteiro

Benech

et al. 2009

Arq. Bras. Med. Vet. Zootec.

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The histological changes of the liver in ewes with pregnancy toxemia were characterized. Ten ewes were fed on grass ad libitum, and another ten were starved from day 130 of pregnancy for up to four days. Liver puncture biopsies were performed at days 70, 100, 130, and 140 of pregnancy, and at day 45 in postpartum. Seric hydroxybutyrate (HB), non-esterified fatty acids (NEFA), aspartate aminotransferase, and alkaline phosphatase were dosed. Histological preparations revealed similar incidence and intensity of mild liver steatosis in both groups at day 130. Starved ewes become toxemic (as indicated by HB), and at day 140 exhibited more severe injury in a higher proportion (9/9 vs. 4/10; P<0.01). Almost all of them (7/9) had large amounts of small lipid droplets in almost every hepatocyte over the whole liver acinus, and higher NEFA values. At day 45 in postpartum, both groups had mild steatotic changes as initially. A positive correlation between severity of liver damage seric and only aspartate aminotransferase was observed at day 140 in starved animals (P<0.05). This enzyme could be used to assess liver damage, but not alkaline phosphatase. All samples with degeneration corresponded to the microvesicular type. A short starvation period during late pregnancy in ewes produced reversible liver degeneration. (9/9 vs. 4/10; P<0,01)

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Histological changes of the liver and metabolic correlates in ewes with pregnancy toxemia

Cal

Borteiro

Benech

et al. 2009

Arq. Bras. Med. Vet. Zootec.

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“…The main adverse effects of amiodarone include hypotension, thyroid toxicity (hyper‐ or hypothyroidism), pulmonary toxicity including bronchiolitis and pulmonary fibrosis, and hepatic lesions such as steatosis, steatohepatitis, and cirrhosis (Dusman et al. 1990; Fromenty and Pessayre 1995; Santangeli et al. 2012).…”

Section: Introductionmentioning

confidence: 99%

“…2012). Numerous studies have shown that mitochondrial dysfunction is a major mechanism of amiodarone‐induced toxicity in liver and other tissues (Fromenty and Pessayre 1995; Di Matola et al. 2000; Nicolescu et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

Self Cite

194

161

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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.

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“…25 The side chain is metabolized by ␤-oxidation, leading to inhibition of medium-and short-chain fatty acid ␤-oxidation. 26,45 Thus, both drugs are converted by P450 to reactive metabolites that can induce a hypersensitivity reaction in genetically susceptible individuals. Less commonly, they induce a microvesicular steatosis; in mice, this requires much higher doses than those used therapeutically, 27 although one wonders if impaired oxidation of these drugs (in the presence of a competing P450 substrate or in a poor metabolizer) might lead, at least rarely, to the accumulation of sufficient levels of the parent drug to impair ␤-oxidation.…”

Section: Antidepressantsmentioning

confidence: 99%