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A Berson

Publications and source records attributed to A Berson.

At least 73 records · Page 4Linked to original sources
PubMed1990

Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant.

Administration of silymarin (800 mg/kg i.p.) 30 min before carbon tetrachloride (18 microL/kg i.p.) did not modify total hepatic levels of CCl4 and metabolites in mice, but decreased by 40% the in vivo covalent binding of CCl4 metabolites to hepatic lipids at 2 hr. This pretreatment decreased by 60% the exhalation of ethane during the first hour after CCl4, and decreased by 50% the incidence of liver cell necrosis. In vitro, silymarin (800 micrograms/mL) decreased by 50 to 70% various monooxygenase activities, and decreased by 20% the covalent binding of CCl4 metabolites to microsomal proteins. Silymarin (800 micrograms/mL) decreased by 70% in vitro lipid peroxidation mediated by CCl4 metabolites, and decreased by 90% peroxidation mediated by NADPH alone. Silibinin, one of the three isomers composing silymarin, also decreased carbon tetrachloride-induced lipid peroxidation; this effect, however, was less than that of silymarin in vitro, and was more transient in vivo. Pretreatment with silibinin (800 mg/kg i.p.) 30 min before CCl4 (18 microL/kg i.p.) did not improve SGPT activity or liver histology at 24 hr. We conclude that silymarin prevents carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice, firstly, by decreasing the metabolic activation of CCl4, and, secondly, by acting as a chain-breaking antioxidant.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II.

The effects of amiodarone on the respiration of isolated mouse liver mitochondria have been determined. Amiodarone (200 microM) had a biphasic effect on state 4 respiration supported by either glutamate plus malate or succinate. Initially, the respiratory rate was increased. This stimulatory effect was not prevented by oligomycin (an inhibitor of ATP synthase). It was associated with marked accumulation of amiodarone in the mitochondria, and with collapse of the mitochondrial membrane potential. This initial uncoupling effect was followed by a progressive decrease in the state 4 respiration rate, leading eventually to marked inhibition. Preincubation for 5 min with amiodarone (200 microM) also decreased markedly ADP-stimulated (state 3) respiration, ATP production and dinitrophenol-stimulated (uncoupled) respiration supported by glutamate plus malate (which donate electrons to complex I), and respiration supported by succinate (which donate electrons to complex II), but did not affect respiration supported by duroquinol (donating electrons to complex III) or by ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (donating electrons to cytochrome c). Preincubation with amiodarone (150-200 microM) decreased markedly respiration mediated by fatty acids of various chain length and respiration mediated by citrate, a tricarboxylic acid cycle substrate. We conclude that amiodarone has a dual effect on mitochondrial respiration. The initial uncoupling effect is probably due to the entry of protonated amiodarone, releasing a proton in the matrix. Accumulation of amiodarone soon leads to inhibition of the respiratory chain at the levels of complex I and complex II and to decreased ATP formation.

Adenosine Diphosphate↗
PubMed1990

Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial beta-oxidation of fatty acids.

The effects of the R-(-) and S-(+)ibuprofen enantiomers were first studied in vitro with mouse liver mitochondria incubated in the presence of various concentrations of exogenous coenzyme A. In the presence of a low concentration of coenzyme A (2.5 microM), the R-(-)enantiomer (which forms an acylcoenzyme A) inhibited stereoselectively the beta oxidation of [1-14C]palmitic acid but not that of [1-14C]palmitoyl-L-carnitine (which can directly enter the mitochondria). In the presence, however, of a concentration of coenzyme A (50 microM) reproducing that present in liver cell cytosol, both enantiomers (2 mM) slightly inhibited the beta oxidation of [1-14C]palmitic acid and markedly inhibited the beta oxidation of [1-14C]octanoic acid and [1-14C]butyric acid. In vivo, both enantiomers (1 mmol.kg-1) similarly inhibited the formation of [14C]CO2 from [1-14C]fatty acids. Both enantiomers similarly decreased plasma ketone bodies. Both similarly increased hepatic triglycerides, and both produced mild microvesicular steatosis of the liver. We conclude that both ibuprofen enantiomers inhibit beta oxidation of fatty acids in vitro and in vivo. In addition, the R-(-)enantiomer may stereoselectively sequester coenzyme A; at low concentrations of coenzyme A in vitro, this may stereoselectively inhibit the mitochondrial uptake and beta oxidation of long chain fatty acids.

Animals↗
PubMed1990

Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Amiodarone↗
PubMed1990

[Unusual cause of ascites: the POEMS syndrome].

A 39-year-old woman presented with polyneuropathy, hepatomegaly, splenomegaly, endocrinopathy, monoclonal protein and skin changes, several of the many clinical features of the recently described POEMS syndrome. In addition, she had a Castleman's disease (angiofollicular lymph node hyperplasia). In this case ascites was a main presenting feature. Thus, the POEMS syndrome must be added to the list of rare causes of ascites. Electron microscopy of the liver showed perisinusoidal fibrosis.

Adult↗
PubMed1990

Inhibition of rat liver estrogen 2/4-hydroxylase activity by troleandomycin: comparison with erythromycin and roxithromycin.

Administration of troleandomycin (0.5 mmol.kg-1 p.o. daily for 5 days) decreased by 61% and 36%, respectively, the estradiol and ethinylestradiol 2/4-hydroxylase activities of hepatic microsomes from male Sprague-Dawley rats killed 2 hr after the last dose. This decrease did not appear to be due to the in vivo formation of the inactive cytochrome P-450 p Fe(II)-metabolite complex, since disruption of this complex with potassium ferricyanide did not increase estrogen hydroxylase activities. Troleandomycin administration, however, essentially suppressed cytochrome P-450 UT-A (one of the P-450 forms involved in the hydroxylation of estrogens) and resulted in the appearance of cytochrome P-450 forms whose estradiol hydroxylase activity was inhibitable by troleandomycin in vitro. Similarly, troleandomycin (2 mM) inhibited by 60% estradiol and ethinylestradiol 2/4-hydroxylase activities in microsomes from dexamethasone-treated rats, although it had no inhibitory effect in microsomes from control rats. In contrast, erythromycin and roxithromycin (2 mM) exerted no inhibitory effect, even in microsomes from dexamethasone-treated rats. In vivo, these macrolides (0.5 mmol.kg-1 p.o. daily for 5 days) decreased moderately cytochrome P-450 UT-A levels and estradiol 2/4-hydroxylase activity, and did not modify ethinylestradiol 2/4-hydroxylase activity. We conclude that the administration of troleandomycin, but not that of erythromycin or roxithromycin, decreases ethinylestradiol 2/4-hydroxylase activity in male rat liver microsomes, as a possible consequence of decreased cytochrome P-450 UT-A levels and of the induction of glucocorticoid-responsive P-450 forms whose ethinylestradiol hydroxylase activity is inhibitable by troleandomycin.

Animals↗
PubMed1989

Inhibitory effects of nilutamide, a new androgen receptor antagonist, on mouse and human liver cytochrome P-450.

The effects of nilutamide were studied first with human liver microsomes. At concentrations expected in the human liver (110 microM), nilutamide inhibited hexobarbital hydroxylase, benzphetamine N-demethylase, benzo(a)pyrene hydroxylase and 7-ethoxycoumarin O-deethylase activities by 85, 40, 35 and 25%, respectively. There was no in vitro inhibition of NADPH-cytochrome c reductase activity, no in vitro loss of CO-binding cytochrome P-450, and no spectral evidence for the in vitro formation of a possible cytochrome P-450Fe(II)-nitroso metabolite complex. Other studies were performed with mouse liver microsomes. Nilutamide (550 microM) did not significantly increase the consumption of NADPH by aerobic microsomes, and did not modify the kinetics for the reduction of cytochrome P-450 by NADPH-cytochrome P-450 reductase in an anaerobic system. Nilutamide (22 microM) produced either a type I or a type II binding spectrum. Kinetics for the inhibition of hexobarbital hydroxylase were consistent with competitive inhibition. A last series of experiments was performed after administration of nilutamide in mice. Thirty minutes after administration of doses (15 or 30 mumol.kg-1 i.p.) similar to those used in humans, the hexobarbital sleeping time was increased by 40 and 60%, respectively. There was no evidence, however, for the irreversible inactivation of microsomal enzymes since CO-binding cytochrome P-450 and monooxygenase activities remained unchanged in liver microsomes from mice killed 1 or 6 hr after administration of nilutamide (30 mumol.kg-1 i.p.). These results show that nilutamide inhibits hepatic cytochrome P-450 activity, and suggest that inhibition may actually occur after therapeutic doses of nilutamide in humans.

Androgen Receptor Antagonists↗
PubMed1989

Genetic predisposition to drug hepatotoxicity: role in hepatitis caused by amineptine, a tricyclic antidepressant.

Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathione concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.

Adolescent↗
PubMed1989

Genetically determined oxidation polymorphism and drug hepatotoxicity. Study of 51 patients.

The influence of genetically determined oxidation polymorphism on drug hepatotoxicity has been poorly investigated and results are controversial. We studied drug oxidation capacity in 51 patients with hepatitis caused mainly by drugs undergoing oxidative metabolism, using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan (the main oxidative metabolite), after oral administration of 40 mg dextromethorphan hydrobromide. Dextromethorphan oxidation capacity was similar in patients and in 103 control subjects as judged by: (a) the prevalence of each phenotype (5.9% versus 3.9% for the poor metabolizer phenotype and 94.1% versus 96.1% for the extensive metabolizer phenotype; (b) the frequency distribution histograms of log metabolic ratio; (c) the mean values of dextromethorphan and dextrorphan urinary outputs and of log metabolic ratio for each phenotype. These results show that hepatotoxicity of several drugs, including amineptine, amodiaquine and Plethoryl, is related neither to an impairment in dextromethorphan oxidation capacity nor to an unusually high capacity to oxidize this drug.

Adolescent↗
PubMed1988

Peliosis hepatis induced by 6-thioguanine administration.

A patient with acute myeloblastic leukaemia developed jaundice revealing peliosis hepatis after receiving 6-thioguanine for two months. Peliosis hepatis was severe and was associated with mild lesions of centrilobular veins. Withdrawal of 6-thioguanine was followed by a progressive improvement of liver dysfunction. This report shows that 6-thioguanine, a thiopurine already reported to be responsible for veno-occlusive disease of the liver, can induce peliosis hepatis. This suggests that some liver vascular disorders caused by thiopurines (6-thioguanine, azathioprine and 6-mercaptopurine), particularly peliosis hepatis, veno-occlusive disease, sinusoidal dilatation and perisinusoidal fibrosis, might be related syndromes caused by similar lesions at different sites.

Chemical and Drug Induced Liver Injury↗
PubMed1988

Team approach enables frail elderly to stay home.

St. Vincent's Hospital and Medical Center of New York has been caring for homebound frail elderly persons since 1973 through a comprehensive network of professional, paraprofessional, and community services that allows many older persons to remain in their homes and communities and avoid institutionalization. The staff consists of physician-nurse-social worker teams that bring to each patient their individual skills as professional practitioners. In addition, working together, they create and attempt to carry out a complete, flexible plan of care. The Chelsea-Village Program (CVP) is open to all persons who the team believes are capable of being maintained independently or who can obtain the necessary additional support of family, friends, or neighbors. The patients, whose average age is 83, are homebound due to orthopedic disorders, arthritis, stroke, chronic cardiac and pulmonary disease, or generalized debility and weakness. St. Vincent's and donations from foundations and individuals fund the program, which is free of charge to its patients. In 1988 about 10 physicians, some in private practice, participated during a typical month; subspecialists have made themselves available; and resident physicians share in the work. The staff has come to understand that human beings are most fulfilled when they are able to use their personal resources in independence and that they must ask the patients for their own definitions of life's goals and serve them as they seek those goals.

Aged↗
PubMed1988

Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.

Microvesicular steatosis of the liver has been reported in two subjects receiving amineptine (a tricyclic antidepressant metabolized by beta-oxidation of its acyl chain). A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation, or in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of amineptine on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation was inhibited by 27, 33, 46 and 57% respectively, in the presence of 0.25, 0.5, 1 and 2 mM of amineptine. Inhibition was reversible. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetyl coenzyme A by mouse liver mitochondria, was inhibited by 22, 23, 47, 54, 60 and 62%, respectively, in the presence of 0.0625, 0.125, 0.25, 0.5, 1 and 2 mM of amineptine. In vivo, administration of amineptine, 0.5 and 0.75 mmol.kg-1, inhibited by 70 and 84%, respectively, the exhalation of [14C] CO2 during the first 3 hr after the administration of a tracer dose of [U-14C]palmitic acid. Administration of amineptine, 0.0625, 0.25, 0.5 or 1 mmol.kg-1, 6 hr before the measurement, increased hepatic triglycerides by 73, 139, 295 and 320%, respectively. After 1 mmol.kg-1, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 5-fold the control value; liver histology at that time showed microvesicular steatosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyl Coenzyme A↗
PubMed1988

[Hepatitis probably caused by Plethoryl. Apropos of 7 cases].

Seven patients developed acute hepatitis after receiving Plethoryl for obesity for 4 to 16 weeks. Jaundice was generally associated with or preceded by asthenia, nausea and pruritus. Serum aminotransferase activities were markedly increased whereas alkaline phosphatase and gamma-glutamyltransferase activities were moderately elevated. There was no hepatic failure. In all cases, Plethoryl administration was promptly discontinued. In 6 cases, jaundice disappeared within 2 to 4 weeks, and recovery occurred within 2 to 5 months. In one case, however, jaundice disappeared within 12 weeks and recovery took 10 months.

Acute Disease↗
PubMed1987

Polymorphism of dextromethorphan oxidation in a French population.

Genetically-controlled drug oxidation capacity was studied using dextromethorphan, an anti-tussive drug, as the test compound in 103 healthy white French subjects (61 males and 42 females). Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan, after oral administration of 40 mg (113.6 mumol) of dextromethorphan hydrobromide. The log MR was bimodally distributed: 99 subjects (96.1%) were phenotyped as extensive metabolizers; they had a log MR between -3.1 and -1.1, a urinary output of dextromethorphan below 5 mumol 10 h-1 and a urinary output of dextrorphan above 20 mumol 10 h-1. Four subjects (3.9%) were phenotyped as poor metabolizers; they had a log MR between -0.5 and +0.7, a urinary output of dextromethorphan above 5 mumol 10 h-1 and a urinary out of dextrorphan below 20 mumol 10 h-1.

Adult↗