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Biomedical subjects

D Pessayre

Publications and source records attributed to D Pessayre.

At least 37 records · Page 2Linked to original sources
PubMed1999

Hepatotoxicity due to mitochondrial dysfunction.

Mitochondria are involved in fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, which provide most of the cell energy. Mitochondria are also the main source of reactive oxygen species in the cell and are involved in cell demise through opening of the mitochondrial permeability transition pore. It was therefore to be expected that mitochondrial dysfunction could be a major mechanism of drug-induced liver disease. Microvesicular steatosis (which may cause liver failure, coma, and death) is the consequence of severe impairment of mitochondrial beta-oxidation. Endogenous compounds (such as cytokines or female sex hormones) or xenobiotics (including toxins such as ethanol and drugs such as aspirin, valproic acid, ibuprofen, or zidovudine) can inhibit beta-oxidation directly or through a primary effect on the mitochondrial genome or the respiratory chain itself. In some patients, infections and cytokines, or inborn errors of beta-oxidation enzymes or the mitochondrial genome, may favor the appearance of drug-induced microvesicular steatosis. Nonalcoholic steatohepatitis may develop under conditions causing prolonged, microvesicular, and/or macrovacuolar steatosis. In this condition, chronic impairment of mitochondrial beta-oxidation (causing steatosis) and the respiratory chain (increasing the production of ROS) lead to lipid peroxidation, which, in turn, may cause the diverse lesions of steatohepatitis, namely, necrosis, inflammation, Mallory's bodies, and fibrosis. Finally, mitochondria are involved in several forms of drug-induced cytolytic hepatitis, through inhibition or uncoupling of respiration or through a drug-induced or reactive metabolite-induced mitochondrial permeability transition. The latter effect commits hepatocytes to either apoptosis or necrosis, depending on the number of organelles that have undergone the permeability transition.

Animals↗
PubMed1999

Mesalazine (5-aminosalicylic acid) induced chronic hepatitis.

BACKGROUND: Treatment of ulcerative colitis or Crohn's disease with sulphasalazine causes several adverse effects, including hepatitis. Sulphasalazine is cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine. Received wisdom was that 5-aminosalicylic acid was topically active, whereas sulphapyridine was absorbed and caused immunoallergic side effects. Mesalazine, a slow release formulation of 5-aminosalicylic acid, was expected to be a safe alternative. However, several cases of acute hepatitis have been reported. CASE REPORT: A 65 year old man had increased liver enzymes, anti-nuclear and anti-smooth muscle autoantibodies and IgG levels, and lesions of chronic hepatitis after 21 months of mesalazine treatment. Although liver dysfunction had been identified eight months earlier, simvastatin rather than mesalazine had been withdrawn, without any improvement. In contrast, liver enzyme and IgG levels became normal and autoantibodies disappeared after discontinuation of mesalazine administration. CONCLUSION: Contrary to initial expectations, mesalazine can cause most of the sulphasalazine induced adverse effects, and hepatic side effects may be almost as frequent. When liver dysfunction occurs, mesalazine administration should be discontinued to avoid the development of chronic hepatitis and liver fibrosis.

Aged↗
PubMed1999

Interleukin-2 overexpresses c-myc and down-regulates cytochrome P-450 in rat hepatocytes.

The interaction of interleukin-2 (IL-2) with its receptor (IL-2R) decreases cytochrome P-450 (CYP) expression in rat hepatocytes. Because IL-2 increases c-Myc in lymphocytes and because c-myc overexpression represses several genes, we postulated that the IL-2/IL-2R interaction may increase c-Myc and thereby down-regulate CYP in hepatocytes. Cultured rat hepatocytes were exposed for 24 h to IL-2 (350 U/ml) and other agents. IL-2 increased c-myc mRNA and protein but decreased total CYP and the mRNAs and proteins of CYP2C11 and CYP3A. The IL-2-mediated c-myc overexpression and CYP down-regulation were prevented by 1) genistein (a tyrosine kinase inhibitor that blocks the initial transduction of the IL-2R signal), 2) retinoic acid, butyric acid, or dimethyl sulfoxide (three agents that block c-myc transcription), or 3) an antisense c-myc oligonucleotide (which may cause rapid degradation of the c-myc transcript). It is concluded that IL-2 causes the overexpression of c-myc and the down-regulation of CYPs in rat hepatocytes. Block of c-myc overexpression, at three different levels with five different agents, prevents CYP down-regulation, suggesting that c-myc overexpression may directly or indirectly repress CYP in hepatocytes.

Animals↗
PubMed1998

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

BACKGROUND & AIMS: 4,4'-Diethylaminoethoxyhexestrol (DEAEH), amiodarone, and perhexiline cause steatohepatitis in humans. The mechanisms of these effects are unknown for DEAEH and have not been completely elucidated for amiodarone and perhexiline. The aim of this study was to determine these mechanisms. METHODS: Rat liver mitochondria, cultured rat hepatocytes, or rats were treated with these drugs, and the effects on mitochondrial respiration, beta-oxidation, reactive oxygen species formation, and lipid peroxidation were determined. RESULTS: DEAEH accumulated in mitochondria and inhibited carnitine palmitoyl transferase I and acyl-coenzyme A dehydrogenases; it decreased beta-oxidation and caused lipid deposits in hepatocytes. DEAEH also inhibited mitochondrial respiration and decreased adenosine triphosphate (ATP) levels in hepatocytes. DEAEH, amiodarone, and perhexiline augmented the mitochondrial formation of reactive oxygen species and caused lipid peroxidation in rats. CONCLUSIONS: Like amiodarone and perhexiline, DEAEH accumulates in mitochondria, where it inhibits both beta-oxidation (causing steatosis) and respiration. Inhibition of respiration decreases ATP and also increases the mitochondrial formation of reactive oxygen species. The latter oxidize fat deposits, causing lipid peroxidation. We suggest that ATP depletion and lipid peroxidation may cause cell death and that lipid peroxidation products may account, in part, for other steatohepatitis lesions.

Animals↗
PubMed1997

Acute hepatitis caused by alverine associated with anti-lamin A and C autoantibodies.

We report the case of a 67-year-old woman in whom onset and regression of acute hepatitis were closely related to the time of administration and withdrawal of the smooth muscle relaxant alverine. Antinuclear antibodies were positive, and their titer followed the course of hepatitis. They presented a smooth rim-like nuclear immunofluorescence staining pattern. Immunoblot assay showed that they were directed against lamin A and lamin C. This suggests that alverine should be added to the list of drugs known to produce acute hepatitis, and that drug-induced liver injury is a possible cause of antinuclear antibodies specific for lamin A and lamin C.

Acute Disease↗
PubMed1997

Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients.

BACKGROUND/AIMS: A 4977-base pair deletion has been detected in the hepatic mitochondrial DNA of alcoholic patients with microvesicular steatosis, a lesion ascribed to impaired mitochondrial beta-oxidation. However, only a single deletion had been looked for in this previous study, and it could not be determined whether the deletion was preexisting or acquired. Alcohol abuse increases the formation of reactive oxygen species in hepatic mitochondria. If this effect accelerates the oxidative aging of mitochondrial DNA, several other mutations would be expected. METHODS: The mtDNA region extending from nucleotide 8167 to nucleotide 14246 was screened for the presence of large mitochondrial DNA deletions in 58 alcoholic patients and 67 age-matched non-alcoholic controls. Hepatic DNA was subjected to polymerase chain reactions that amplified non-deleted and deleted mitochondrial DNA, respectively, and the boundaries of the mitochondrial DNA deletions were sequenced. RESULTS: Only 3% of the non-alcoholic controls carried a mitochondrial DNA deletion, whereas 24% of all alcoholic patients and 85% of the 13 alcoholic patients with microvesicular steatosis exhibited either single or multiple 4977, 5385, 5039 and 5556-base pair mitochondrial DNA deletions. No deletion(s) were observed, however, in 13 patients with microvesicular steatosis due to other causes. CONCLUSIONS: Diverse mitochondrial DNA rearrangements are observed in alcoholic patients with microvesicular steatosis. We suggest that alcohol abuse leads to premature oxidative aging of mitochondrial DNA. Hypothetically, oxidative damage to mitochondrial constituents (DNA, proteins and lipids) may favor microvesicular fat deposition.

Adult↗
PubMed1997

Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines.

Microvesicular steatosis occurs in conditions characterized by severe impairment of the mitochondrial beta-oxidation process, due to genetic and/or acquired causes. Drugs and some endogenous compounds can sequester coenzyme A (aspirin, valproic acid), inhibit mitochondrial beta-oxidation enzymes (tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine), or inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhexestrol), while female sex hormones have complex, but moderate, effects on mitochondrial structure and function. Other substances impair mitochondrial DNA transcription (interferon-alpha) or mitochondrial DNA replication (dideoxynucleosides), while alcohol abuse might accelerate the normal oxidative aging of mitochondrial DNA. When beta-oxidation is severely impaired, fatty acids, which are poorly oxidized by mitochondria, are mainly esterified into triglycerides, but there is a residual increase in non-esterified fatty acids. Triglycerides (possibly emulsified by a rim of non-esterified fatty acids) accumulate as small vesicles. Impairment of energy production, and the mitochondrial and general toxicity of both non-esterified fatty acids and dicarboxylic acids, may contribute to liver failure, coma and death in severe forms. Although milder forms of microvesicular steatosis have a good short-term prognosis, they can lead to chronic lipid peroxidation and the development of steatohepatitis lesions. Investigational molecules with a carboxylic group or a protonatable amine, or those which might interfere with mitochondrial DNA, should be screened for possible mitochondrial effects.

Animals↗
PubMed1997

Premature oxidative aging of hepatic mitochondrial DNA in Wilson's disease.

BACKGROUND & AIMS: Aging is associated with and may be caused by acquired somatic mutations of the mitochondrial genome. In Wilson's disease, inherited mutations of a nuclear gene encoding a copper transporter cause accumulation of copper in the liver, particularly within mitochondria. Because copper has prooxidant properties and the mitochondrial genome is particularly susceptible to oxidative damage, we hypothesized that Wilson's disease may cause premature oxidative aging of mitochondrial DNA. METHODS: Hepatic DNA was screened for large mitochondrial DNA deletion(s) in 16 patients with Wilson's disease and 67 control subjects. Deleted mitochondrial DNA copies were amplified by polymerase chain reaction and were sequenced. RESULTS: Although 15 of the 16 patients with Wilson's disease were 30 years old or younger, 8 of them (50%), including the 6 patients with cirrhosis (100%), had diverse mitochondrial DNA deletions, whereas only 2 controls (3%), aged 39 and 45 years, showed a mitochondrial DNA deletion. CONCLUSIONS: Wilson's disease is associated with frequent, diverse, and early deletions of mitochondrial DNA. Accumulation of prooxidant copper within hepatic mitochondria may cause this premature oxidative aging of mitochondrial DNA. Thus, inherited mutations of a nuclear gene may cause somatic mutations of the mitochondrial genome in this condition.

Adolescent↗
PubMed1997

Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes.

BACKGROUND & AIMS: Germander was withdrawn from the market after its use for weight control caused an epidemic of hepatitis. Its toxicity was shown to be caused by diterpenoids and their cytochrome P4503A-mediated metabolic activation into electrophilic metabolites that deplete cellular thiols. The aim of the present study was to determine the mechanisms of cell death. METHODS: Isolated rat hepatocytes were incubated for 2 hours with germander diterpenoids (100 micrograms/mL). RESULTS: Diterpenoids decreased cell glutathione, increased cytosolic [Ca2+], activated Ca(2+)-dependent tissue transglutaminase forming a cross-linked protein scaffold, and caused internucleosomal DNA fragmentation and the ultrastructural features of apoptosis. Cell death was prevented by decreasing metabolic activation (with troleandomycin), preventing depletion of glutathione (with cystine), blocking activation of Ca(2+)-modulated enzymes (with calmidazolium), or inhibiting internucleosomal DNA fragmentation (with aurintricarboxylic acid). Apoptosis was increased and diterpenoids caused overexpression of p53 and interleukin 1 beta-converting enzyme in rats treated with dexamethasone (cytochrome P4503A inducer). Apoptosis was also increased by a diet deficient in sulfur amino acids. CONCLUSIONS: The germander furano diterpenoids cause apoptosis within 2 hours in isolated rat hepatocytes. Electrophilic metabolites may stimulate apoptosis by decreasing thiols, increasing [Ca2+], and activating Ca(2+)-dependent transglutaminase and endonucleases.

Amino Acids, Sulfur↗
PubMed1997

In vivo assessment of lipid peroxidation in experimental edematous and necrotizing rat pancreatitis.

Lipid peroxidation, which may be involved in the pathogenesis of acute pancreatitis, is usually assessed in vitro or indirectly using antioxidants or free radical scavengers. We assessed lipid peroxidation in an in vivo model by measuring ethane exhalation in two models of acute pancreatitis. Edematous acute pancreatitis was induced by a supramaximal intraperitoneal injection of cerulein. Necrotizing acute pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreaticobiliary duct. Rats were placed in closed chambers and ethane exhalation was measured in aliquots. Ethane exhalation was significantly increased (p < 0.002) in cerulein (n = 12)- but not in taurocholate (n = 6)-induced pancreatitis compared to controls (n = 12 and 6, respectively). Our results suggest that free radicals may play a role in the pathogenesis of edematous pancreatitis but do not play an important role in the progression to necrotizing pancreatitis.

Acute Disease↗
PubMed1997

Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation.

Glucocorticoid administration may produce fatty liver in humans. We investigated the effects of dexamethasone on hepatic mitochondria and lipid metabolism in mice. Dexamethasone 21-phosphate (20 microM) did not inhibit the mitochondrial inner membrane-bound very-long-chain acyl-CoA dehydrogenase but inhibited the matrixlocated long-, medium-, and short-chain dehydrogenases. Dexamethasone 21-phosphate (20 microM) inhibited the first beta-oxidation cycle of [1-(14C)]butyric acid and [1-(14C)]octanoic acid but not that of [1-(14C)]palmitic acid. Administration of dexamethasone 21-phosphate (100 mg/kg) decreased the in vivo oxidation of [1-(14C)]butyric acid and [1-(14C)]octanoic acid into [14C]CO2 but not that of [1-(14C)]palmitic acid and decreased the hepatic secretion of triglycerides. After 5 days of treatment (100 mg/kg daily), hepatic triglycerides were increased and both microvesicular steatosis and ultrastructural mitochondrial lesions were present. In conclusion, glucocorticoids inhibit medium- and short-chain acyl-CoA dehydrogenation and hepatic lipid secretion in mice. These effects may account for their steatogenic effects in humans.

Acyl-CoA Dehydrogenases↗
PubMed1996

Antigenic targets in tienilic acid hepatitis. Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera.

Patients with tienilic acid hepatitis exhibit autoantibodies that recognize unalkylated cytochrome P450 2C9 in humans but recognize 2C11 in rats. Our aim was to determine whether the immune reaction is also directed against neoantigens. Rats were treated with tienilic acid and hepatocytes were isolated. Immunoprecipitation, immunoblotting, and flow cytometry experiments were performed with an anti-tienilic acid or an anti-cytochrome P450 2C11 antibody. Cytochrome P450 2C11 was the main microsomal or plasma membrane protein that was alkylated by tienilic acid. Inhibitors of vesicular transport decreased flow cytometric recognition of both unalkylated and tienilic acid-alkylated cytochrome P450 2C11 on the plasma membrane of cultured hepatocytes. Tienilic acid hepatitis sera that were preadsorbed on microsomes from untreated rats (to remove autoantibodies), poorly recognized untreated hepatocytes in flow cytometry experiments, but better recognized tienilic acid-treated hepatocytes. This recognition was decreased by adsorption with tienilic acid or by preexposure to the anti-tienilic acid or the anti-cytochrome P450 2C11 antibody. We conclude that cytochrome P450 2C11 is alkylated by tienilic acid and follows a vesicular route to the plasma membrane. Tienilic acid hepatitis sera contain antibodies against this tienilic acid adduct, in addition to the previously described anticytochrome P450 autoantibodies.

Alkylation↗