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D Larrey

Publications and source records attributed to D Larrey.

At least 199 records · Page 11Linked to original sources
PubMed1986

Effects of pregnancy on the toxicity and metabolism of acetaminophen in mice.

Although acetaminophen is widely used in pregnant women, the effects of pregnancy on its hepatotoxicity remain unknown. We assessed these effects in pregnant mice (17-18 days of gestation). The hepatotoxicity of acetaminophen (300-400 mg X kg-1 i.p.) was increased markedly in pregnant mice, as judged by increased serum glutamic-pyruvic transaminase activity, higher incidence of liver necrosis and greater mortality. In vitro, acetaminophen sulfotransferase activity was increased by 47% in pregnant mice, but acetaminophen glucuronosyltransferase activity was decreased by 54%; the metabolic activation of acetaminophen to covalently bound metabolites was unchanged. Glutathione S-transferase activities were decreased slightly. In vivo, after administration of acetaminophen (300 mg X kg-1 i.p.), the 24-hr urinary excretion of the sulfate conjugate was increased (from 12% of the recovered dose in nonpregnant mice to 21% in pregnant mice), that of the glucuronide was decreased (from 61 to 52%), whereas those of the cysteine and mercapturic acid conjugates and that of acetaminophen were unchanged. Finally, the plasma clearance and the apparent volume of distribution of acetaminophen (both expressed per body weight) remained unchanged. Similarly, in vivo covalent binding to hepatic proteins 4 hr after administration of acetaminophen (300 and 400 mg X kg-1 i.p.) remained unchanged as were in vivo indexes of lipid peroxidation. In contrast, liver glutathione concentration, albeit initially normal, fell to much lower levels after administration of acetaminophen (200-400 mg X kg-1 i.p.) or diethylmaleate (0.5 ml X kg-1 i.p.) in pregnant mice, and recovered more slowly thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1986

Inactivation and induction of cytochrome P-450 by various psoralen derivatives in rats.

8-Methoxypsoralen has been shown to both inactivate and induce microsomal enzymes. We report here the effects of other psoralen derivatives in rats. CO-binding cytochrome P-450 decreased when hepatic microsomes were incubated for 10 min with an NADPH-generating system and 8-methoxypsoralen, 5-methoxypsoralen or psoralen (400 microM), but remained unchanged with trioxsalen (400 microM). The destruction of cytochrome P-450 with the former derivatives required NADPH. It was greater with microsomes from phenobarbital-pretreated rats. Monooxygenase activities were decreased by 30 to 60% when 8-methoxypsoralen, 5-methoxypsoralen or psoralen (10 or 25 microM) were added to the incubation mixtures, but remained unchanged upon addition of trioxsalen (10 or 25 microM). In vivo, monooxygenase activities were decreased 4 hr after the administration of a single dose of 8-methoxypsoralen, 5-methoxypsoralen or psoralen (125 mumol X kg-1 p.o.) but remained unchanged after trioxsalen (125 mumol X kg-1 p.o.). During repeated administration of 8-methoxypsoralen or 5-methoxypsoralen (125 mumol X kg-1 p.o. for 3 or 4 days), there was evidence for both induction and inactivation of drug-metabolizing enzymes; monooxygenase activities were high or normal late after a preceding dose, but fell again to normal or low values, respectively, early after a further dose. With psoralen, there was only inactivation, and monooxygenase activities tended to remain low throughout. Monooxygenase activities remained normal with trioxsalen. We conclude that 5-methoxypsoralen, like 8-methoxypsoralen, both inactivates and induces microsomal enzymes. In contrast, psoralen only inactivates them, whereas trioxsalen shows little effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Pre- or post-treatment with methoxsalen prevents the hepatotoxicity of acetaminophen in mice.

We have reported previously that methoxsalen is a suicide substrate for cytochrome P-450. We now report its effects on the metabolism and toxicity of acetaminophen in mice. Intragastric administration of methoxsalen (125 mumol X kg-1), 30 min before that of acetaminophen (600 mg X kg-1 i.p.), decreased the formation of the mercapturate and cysteine conjugates of acetaminophen, the depletion of glutathione and the in vivo covalent binding of an acetaminophen metabolite to hepatic proteins and prevented the increase in serum glutamic-pyruvic transaminase activity, the appearance of liver lesions and mortality. Methoxsalen (250 mumol X kg-1) also afforded complete protection when given intragastrically 2 hr after acetaminophen (600 mg X kg-1 i.p.). At that time, methoxsalen still decreased in vivo covalent binding measured per whole liver, and permitted a faster recovery of hepatic glutathione. Methoxsalen (180 mumol X kg-1) and N-acetylcysteine (919 mumol X kg-1) exerted additive protective effects when given concomitantly 2 hr after acetaminophen. We conclude that administration of methoxsalen decreases the metabolic activation and the hepatotoxicity of acetaminophen in mice.

Acetaminophen↗
PubMed1986

Inactivation of cytochrome P-450 by the drug methoxsalen.

Administration of methoxsalen (50 mumol X kg-1 i.p.) increased 4-fold the hexobarbital sleeping time in rats; at this low dose, SKF 525-A, piperonyl butoxide and cimetidine had little or no effect. In vitro, the concentration of methoxsalen inhibiting by 50% monooxygenase activities ranged from 10 microM (for benzo(a)-pyrene and hexobarbital hydroxylases] to 25 microM for 7-ethoxy-coumarin deethylase and aminopyrine demethylase); these values were in the range of those observed with SKF 525-A (1-50 microM) or piperonyl butoxide (10-100 microM) but much lower than those for cimetidine (100-500 microM). Methoxsalen (25-1000 microM) decreased cytochrome P-450 in vitro, in the presence of EDTA; this effect required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. Similarly, administration of methoxsalen (125 mumol X kg-1 i.p.) decreased cytochrome P-450 and monooxygenase activities in vivo; the decrease in cytochrome P-450 was enhanced by phenobarbital pretreatment and was prevented by piperonyl butoxide. There was no evidence for lipid peroxidation, denaturation into cytochrome P-420, formation of cytochrome P-450-metabolite complexes, destruction of heme or formation of green pigments. In contrast, a reactive metabolite of methoxsalen covalently bound to microsomal proteins; covalent binding required NADPH and oxygen, was decreased by piperonyl butoxide and was increased by phenobarbital pretreatment. We conclude that methoxsalen is activated into a metabolite which destroys cytochrome P-450.

Animals↗
PubMed1985

Regulation of renal cytochrome P-450. Effects of two-thirds hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes.

The possibility of a relationship between hepatic and renal cytochrome P-450 contents was assessed in rats with liver disease. In rats killed 3 days after two-thirds hepatectomy (a model for hepatocellular insufficiency), the total microsomal cytochrome P-450 content of the whole liver was decreased by 60% as compared to that in control rats; renal cytochrome P-450 was increased by 30% while the 7-ethoxycoumarin deethylase activity of kidney microsomes was increased by 80%. In rats killed 7 days after bile duct ligation (a model for cholestasis) or 35 days after bile duct ligation (a model for biliary cirrhosis), hepatic cytochrome P-450 was decreased by 60% and 45%, respectively, while renal cytochrome P-450 content was increased by 50% and 150%, respectively. In contrast, in rats killed 15 days after the last dose of carbon tetrachloride, 1.3 ml/kg twice weekly for 3 months (a model for post-necrotic cirrhosis), both hepatic and renal cytochrome P-450 contents remained unchanged. Phenobarbital (80 mg/kg daily for 3 days) was a poor inducer of renal cytochrome P-450 in sham-operated rats but became a potent inducer of renal cytochrome P-450 in rats with two-thirds hepatectomy. We conclude that renal cytochrome P-450 is increased in three models in which hepatic cytochrome P-450 contents are decreased (two-thirds hepatectomy, cholestasis and biliary cirrhosis), but remains unchanged in a model of severe liver pathology, in which hepatic cytochrome P-450 content is not modified (late, post-necrotic cirrhosis). The hypothetical role of endogenous inducer(s) is discussed.

Animals↗
PubMed1985

Drug interactions and hepatitis produced by some macrolide antibiotics.

Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin. A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins. The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver antigens may be recognized as foreign and may trigger, in an exceptional subject, an immunoallergic type of clinical hepatitis.

Animals↗
PubMed1984

Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism.

Genetic polymorphism in oxidative drug metabolism is perhaps best exemplified in the case of debrisoquine 4-hydroxylase activity, where the incidence of deficient metabolism ranges from 1% to 30% in various populations and this defect is also linked to an impaired ability to metabolize a number of other drugs effectively. Sprague-Dawley (SD) rats possess this activity, but females of the DA strain do not, although total cytochrome P-450 (P-450) levels are similar. We have purified, by using debrisoquine 4-hydroxylase activity as an assay, a minor P-450 to electrophoretic homogeneity from male SD rats and designate this as P-450UT-H. P-450UT-H differs from eight other purified rat liver P-450s as judged by peptide mapping and immunochemical analysis and thus appears to be isozymic with these other P-450s. P-450UT-H exhibited considerably more debrisoquine 4-hydroxylase activity than any of the other purified P-450s and, on a total P-450 basis, more than total microsomal P-450. Antibodies raised against P-450UT-H specifically recognized P-450UT-H and inhibited more than 90% of the debrisoquine hydroxylase activity present in SD rat liver microsomes. The level of P-450UT-H in SD rat liver microsomes accounted for less than 10% of the total P-450, as judged by immunochemical quantitation. These assays also indicated that the level of P-450UT-H in female DA rat liver microsomes is only about 5% of that in male or female SD rat liver microsomes, consonant with the view that deficiency of this form of P-450 is responsible for the defective debrisoquine 4-hydroxylase activity in the former animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Recurrent jaundice caused by recurrent hyperemesis gravidarum.

The existence of jaundice induced by hyperemesis gravidarum is controversial. We report the case of a woman who suffered from three episodes of jaundice during the first trimester of three consecutive pregnancies, a few days after the onset of hyperemesis gravidarum. Jaundice was caused by conjugated hyperbilirubinaemia. Serum alanine aminotransferase activity was increased and scarce necrotic hepatocytes were shown on light and electron microscopic examinations. Cessation of vomiting was rapidly followed by complete recovery. This observation supports the view that severe vomiting can cause jaundice in pregnant women.

Adult↗
PubMed1983

Purification and characterization of six cytochrome P-450 isozymes from human liver microsomes.

Six cytochrome P-450 (P-450) isozymes were purified to electrophoretic homogeneity from the livers of four human organ donors, with three of these isozymes purified from a single individual. Differences were noted between all six P-450s for some or all of the parameters determined by the techniques of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, peptide mapping, spectral analysis of ferrous-carbon monoxide complexes, double-diffusion immunoprecipitin analysis or crossed immunoelectrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis/peroxidase-coupled staining) with rabbit antisera raised to five of the P-450s, or catalytic activity toward d-benzphetamine, benzo[a]pyrene, acetanilide, debrisoquine, (R)- and (S)-warfarin, and 1-naphthylamine. While NADPH-fortified human liver microsomal preparations showed catalytic activity toward trichloroethylene, 7-ethoxycoumarin, 2-naphthylamine, and 2-aminofluorene in addition to the other substrates mentioned, none of the P-450s which we purified from these microsomes catalyzed the oxidation of these compounds in reconstituted enzyme systems containing purified rat liver NADPH-P-450 reductase. Antibodies raised against one of the purified P-450s inhibited d-benzphetamine N-demethylase activity in microsomal incubations but did not inhibit the metabolism of 7-ethoxycoumarin, acetanilide, benzo[a]pyrene, or debrisoquine. The data provide a strong biochemical basis for the view that distinct isozymes of P-450 exist in humans and that these isozymes differ in catalytic activity toward drugs and carcinogens.

Adult↗
PubMed1983

Formation of inactive cytochrome P-450 Fe(II)-metabolite complexes with several erythromycin derivatives but not with josamycin and midecamycin in rats.

The effects of some macrolides (4 mmoles . kg-1 p.o. daily for 4 days in vivo; 0.3 mM in vitro) on hepatic drug-metabolizing enzymes in rats were compared. One group of macrolides including previously studied compounds (oleandomycin, erythromycin and troleandomycin), as well as several other erythromycin derivatives, showed induction of microsomal enzymes and formation of inactive cytochrome P-450-metabolite complexes in vivo; this formation increased in the order: oleandomycin, erythromycin ethylsuccinate, erythromycin stearate, erythromycin itself, erythromycin propionate, erythromycin estolate and troleandomycin. Troleandomycin and, to a lesser extent, erythromycin and oleandomycin formed cytochrome P-450-metabolite complexes when incubated in vitro with 1 mM NADPH and microsomes from rats pretreated with troleandomycin or phenobarbital, but not with microsomes from control rats or rats treated with 3-methylcholanthrene. In contrast, two other macrolides, josamycin and midecamycin, showed no induction of microsomal enzymes and no detectable formation of cytochrome P-450-metabolite complexes in vivo. In vitro, these macrolides failed to form detectable complexes even with microsomes from rats pretreated with troleandomycin or phenobarbital. Hexobarbital sleeping time was unaffected by preadministration of josamycin or midecamycin (4 mmoles . kg-1 p.o.) 2 hr earlier; the in vitro activity of hexobarbital hydroxylase was not inhibited by 0.3 mM josamycin or midecamycin. We conclude that, unlike several erythromycin derivatives, josamycin and midecamycin do not form inactive cytochrome P-450-metabolite complexes in rats.

Animals↗
PubMed1983

Effects of erythromycin on hepatic drug-metabolizing enzymes in humans.

In rats, erythromycin has been shown to induce microsomal enzymes and to promote its own transformation into a metabolite which forms an inactive complex with reduced cytochrome P-450. To determine whether similar effects also occur in humans, we studied hepatic microsomal enzymes from six untreated patients and six patients treated with erythromycin propionate, 2 g per os daily for 7 days. In the treated patients, NADPH-cytochrome c reductase activity was increased; the total cytochrome P-450 concn was also increased but part of the total cytochrome P-450 was complexed by an erythromycin metabolite. The concn of uncomplexed (active) cytochrome P-450 was not significantly modified and the activity of hexobarbital hydroxylase remained unchanged. We also measured the clearance of antipyrine in six other patients; this clearance was not significantly decreased when measured again on the seventh day of the erythromycin propionate treatment. We conclude that the administration of erythromycin propionate induces microsomal enzymes and results in the formation of an inactive cytochrome P-450-metabolite complex in humans. However, the concn of uncomplexed (active) cytochrome P-450 and tests for in vitro and in vivo drug metabolism were not significantly modified.

Adult↗
PubMed1983

Propranolol does not further decrease the clearance of antipyrine in patients with alcoholic cirrhosis.

We determined the clearance of antipyrine before, and during, the administration of propranolol in eight male patients with alcoholic cirrhosis and a recent episode of gastrointestinal bleeding. The clearance of antipyrine in these patients was markedly reduced as compared with that in eight male, age-matched control subjects but was not further decreased after 1 month of propranolol administration. Antipyrine is the prototype of a drug with a low hepatic clearance. We suggest that the hepatic metabolism of some low clearance drugs may not be further decreased when patients with alcoholic cirrhosis are placed on propranolol therapy for the prevention of recurrent gastrointestinal bleeding.

Adult↗
PubMed1983

Inactivation of cytochrome P-450 by a troleandomycin metabolite. Protective role of glutathione.

Troleandomycin, a macrolide antibiotic, has been shown to be demethylated and oxidized into a metabolite which forms an inactive complex with the iron(II) of cytochrome P-450. The role of glutathione in the metabolism of troleandomycin was investigated. Administration of troleandomycin (1 mmol X kg-1 p.o.) decreased the concentration of glutathione in the liver. The depletion of glutathione was increased in rats pretreated with phenobarbital and decreased in rats pretreated with CoCl2. In vitro, an inverse relationship was found between the concentration of glutathione in the incubation mixture and the appearance of the cytochrome P-450-troleandomycin metabolite complex. Glutathione, however, did not inhibit the demethylation of troleandomycin and did not destroy the cytochrome P-450-troleandomycin metabolite complex. The in vitro protective effect of glutathione was reproduced by cysteine but not by glycine. In vivo, decreasing the concentration of glutathione in the liver by food deprivation or by the administration of diethylmaleate increased the formation of the cytochrome P-450-troleandomycin metabolite complex. These results indicate that glutathione is depleted by a troleandomycin metabolite in vivo, whereas glutathione protects against the formation of the inactive cytochrome P-450-troleandomycin metabolite complex in vitro and in vivo.

Animals↗
PubMed1982

Formation of an inactive cytochrome P-450 Fe(II)-metabolite complex after administration of troleandomycin in humans.

In rats, it has been shown that troleandomycin induces its own transformation into a metabolite forming an inactive complex with reduced cytochrome P-450. To determine whether similar effects occur in humans, we studied hepatic microsomes from 6 untreated patients and 6 patients treated with troleandomycin, 2 g per os daily for 7 days. In the treated patients, NADPH-cytochrome c reductase activity was increased by 48%; total cytochrome P-450 concentration was also increased, but 33% of total cytochrome P-450 was complexed by a troleandomycin metabolite. The cytochrome P-450 Fe(II)-metabolite complex exhibited properties identical to those of the inactive complex formed in rats: it exhibited a Soret peak at 456 nm, was unable to bind CO, and was destroyed by addition of 50 microM potassium ferricyanide. We also measured the clearance of antipyrine in 6 other subjects. This clearance was decreased by 45% when measured again on te seventh day of the troleandomycin treatment. We conclude that repeated administration of troleandomycin induces microsomal enzymes, produces an inactive cytochrome P-450 Fe(II)-metabolite complex, and decreases the clearance of antipyrine in humans.

Adult↗
PubMed1982

Hepatotoxicity of trichloroethylene-carbon tetrachloride mixtures in rats. A possible consequence of the potentiation by trichloroethylene of carbon tetrachloride-induced lipid peroxidation and liver lesions.

Liver histology was normal 24 h after the administration of trichloroethylene (1 ml . kg-1) in rats. It was normal, or showed necrosis of a few hepatocytes, after the administration of carbon tetrachloride (64 microliters . kg-1). In rats receiving both solvents, there was extensive centrilobular necrosis. In vitro, trichloroethylene did not initiate lipid peroxidation but potentiated that initiated by carbon tetrachloride; a similar potentiating effect was observed for a wide range of trichloroethylene concentrations (0.19-12 mM). In vivo, a wide range of trichloroethylene doses (0.064-1 ml . kg-1) similarly potentiated the hepatotoxicity of carbon tetrachloride. Administration of trichloroethylene (1 ml . kg-1), 5 h earlier, increased carbon tetrachloride-induced lipid peroxidation in vitro, and increased the hepatotoxicity of a subsequent dose of carbon tetrachloride (64 microliters . kg-1). Previous administration of carbon tetrachloride failed to modify lipid peroxidation and to increase the hepatotoxicity of trichloroethylene. We conclude that trichloroethylene potentiates the hepatotoxicity of carbon tetrachloride, possibly by increasing carbon tetrachloride-induced lipid peroxidation.

Animals↗