Metabolic activation of the tricyclic antidepressant amineptine by human liver cytochrome P-450.
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Animals↗
Biomedical subjects
D Pessayre
Publications and source records attributed to D Pessayre.
The drug methoxsalen, a suicide substrate for cytochrome P-450, decreases the metabolic activation, and prevents the hepatotoxicity, of carbon tetrachloride in mice.
Methoxsalen, a potent suicide inhibitor of cytochrome P-450 that can be used in humans, might be of value for the prevention of hepatitis in subjects with carbon tetrachloride poisoning. As a preliminary step, we have determined its effects on the hepatotoxicity of carbon tetrachloride in mice. Several monooxygenase activities, the in vitro covalent binding of carbon tetrachloride metabolites to microsomal proteins, and in vitro microsomal lipid peroxidation initiated by carbon tetrachloride metabolites were decreased by 60-90% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 mumol X kg-1); microsomal lipid peroxidation mediated by endogenous iron and NADPH was not modified. Administration of methoxsalen (250 mumol X kg-1) 30 min before carbon tetrachloride (0.1 ml X kg-1) decreased both the in vivo formation of conjugated dienes in microsomal lipids and the in vivo covalent binding of carbon tetrachloride metabolites to lipids and proteins. This pretreatment completely prevented the hepatotoxicity of carbon tetrachloride. Other cytochrome P-450 inhibitors (cimetidine, SKF 525-A or piperonyl butoxide) given at this low molar dose (250 mumol X kg-1) exerted no protective effect. Methoxsalen (500 mumol X kg-1) was also effective, but only partially, when given 30 min after carbon tetrachloride (0.025 ml X kg-1). We conclude that pretreatment with methoxsalen decreases the metabolic activation of carbon tetrachloride, and completely prevents its hepatotoxicity in mice. Post-treatment with methoxsalen must be given early and is only partially effective in mice.
Alanine Transaminase↗
Inactivation of human liver cytochrome P-450 by the drug methoxsalen and other psoralen derivatives.
The effects of psoralen derivatives on cytochrome P-450 have been studied in human liver microsomes. CO-binding cytochrome P-450 was decreased by 33% after 10 min of incubation with 1.5 mM EDTA, an NADPH-regenerating system and 20 microM methoxsalen (8-methoxypsoralen). No destruction of cytochrome P-450 was observed when either NADPH or methoxsalen was omitted. A similar (27%) decrease in CO-binding required a 100-times higher concentration of allylisopropylacetamide (2 mM). The activities of 7-ethoxycoumarin deethylase and benzo(a)pyrene hydroxylase were decreased by about 50% in the presence of 12.5 microM methoxsalen. At this low concentration, neither cimetidine nor SKF 525-A or piperonyl butoxide had any significant inhibitory effect. Monooxygenase activities were also decreased in the presence of 12.5 microM bergapten (5-methoxypsoralen) or 12.5 microM psoralen, but not with 12.5 microM trioxsalen (trimethylpsoralen). CO-binding cytochrome P-450 was not decreased after 10 min of incubation with 1.5 mM EDTA, an NADPH-regenerating system and 20 microM trioxsalen. We conclude that methoxsalen is an extremely potent suicide inhibitor of cytochrome P-450 in human liver microsomes. Bergapten and psoralen are also inhibitory whereas trioxsalen has little effects. In the latter derivative, a methyl group is attached on the furan ring and may hinder its metabolic activation and the inactivation of cytochrome P-450.
5-Methoxypsoralen↗
Metabolic activation of the tricyclic antidepressant amineptine--I. Cytochrome P-450-mediated in vitro covalent binding.
Incubation of [14C]amineptine (1 mM) with hamster liver microsomes resulted in the irreversible binding of an amineptine metabolite to microsomal proteins. Covalent binding measured in the presence of various concentrations of amineptine (0.0625-1 mM) followed Michaelis-Menten kinetics. Pretreatment with phenobarbital increased not only the Vmax, but also the Km, for this binding. Covalent binding required NADPH and molecular oxygen and was decreased when the incubation was made in the presence of inhibitors of cytochrome P-450 such as piperonyl butoxide (4 mM), SKF 525-A (4 mM) or carbon monoxide (80:20 CO-O2 atmosphere). In contrast, binding was increased when microsomes from untreated hamsters were incubated in the presence of 0.5 mM 1,1,1-trichloropropene 2,3-oxide, an inhibitor of epoxide hydrolase. Metabolic activation also occurred in kidney microsomes. In vitro covalent binding to kidney microsomal proteins required NADPH and was decreased by piperonyl butoxide (4 mM) but was not increased by pretreatment with phenobarbital. We conclude that amineptine is activated by hamster liver and kidney microsomes into a chemically reactive metabolite that covalently binds to microsomal proteins.
Animals↗
Metabolic activation of the tricyclic antidepressant amineptine--II. Protective role of glutathione against in vitro and in vivo covalent binding.
Incubation of [11-14C]amineptine (1 mM) with an NADPH-generating system and hamster liver microsomes resulted in the in vitro covalent binding of an amineptine metabolite to microsomal proteins; this binding was decreased by 41-71% in the presence of cysteine, lysine, glycine or glutathione (0.5 mM). An inverse relationship was found between the concentration of glutathione in the incubation mixture (0.25-4 mM) and the extent of covalent binding in vitro, which became undetectable at concentrations of glutathione of 2 mM and higher. Administration of [11-14C]amineptine (300 mg/kg-1 i.p.) to hamsters pretreated with phorone (500 mg/kg i.p.) resulted in the in vivo covalent binding of an amineptine metabolite to hepatic proteins. This binding was increased by phenobarbital-pretreatment and decreased by piperonyl butoxide-pretreatment. After various doses of phorone (150-500 mg/kg), an inverse relationship was found between hepatic glutathione content and in vivo covalent binding. Administration of amineptine alone (300 mg/kg i.p.) depleted hepatic glutathione by 16% only; in these animals, in vivo covalent binding was undetectable from background. Amineptine (300 mg/kg i.p.) did not produce hepatic necrosis, even in hamsters pretreated with phorone and/or phenobarbital. We conclude that physiologic concentrations of glutathione essentially prevent the in vivo covalent binding of an amineptine metabolite to hepatic proteins, and that this binding does not produce liver cell necrosis in hamsters.
Animals↗
Carbamazepine-induced acute cholangitis.
We report the case of a patient with carbamazepine-induced cholestasis in whom histologic examination showed acute cholangitis. This type of lesion broadens the spectrum of carbamazepine-induced liver injury which also includes granuloma and hepatocellular necrosis. Its association with marked hypereosinophilia suggests that carbamazepine may cause acute cholangitis through an immunoallergic mechanism.
Aged↗
Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice.
The effects of methoxsalen, a potent inhibitor of cytochrome P-450, on the hepatotoxicity and nephrotoxicity of chloroform have been determined in mice. Hepatic and renal monooxygenase activities and the in vitro covalent binding of chloroform metabolites to hepatic and renal microsomal proteins were decreased by 20-70% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 mumol.kg-1ip) alone. Administration of methoxsalen (250 mumol.kg-1ip), 30 min before [14C]chloroform (1 ml.kg-1ip), did not modify blood levels of [14C]chloroform (and metabolites) but decreased the in vivo covalent binding of [14C]chloroform metabolites to hepatic and renal proteins 4 hr after the administration of [14C]chloroform. This pretreatment markedly decreased serum glutamic pyruvic transaminase activity, blood urea nitrogen, glucosuria, liver and kidney lesions, and mortality 24 hr after the administration of chloroform (0.125-1.5 ml.kg-1ip). Other cytochrome P-450 inhibitors (SKF 525-A or piperonyl butoxide), given at the same molar dose (250 mumol.kg-1ip), exerted no protective effect. Pretreatment with methoxsalen appears to decrease the metabolic activation of chloroform and essentially prevents its hepatotoxicity and nephrotoxicity in mice. Methoxsalen may have use as a tool to determine the role of metabolic activation by cytochrome P-450 in the hepatotoxicity and nephrotoxicity of drugs and chemicals.
7-Alkoxycoumarin O-Dealkylase↗
Chronic active hepatitis caused by benzarone.
We report a case of chronic active hepatitis caused by benzarone, a benzofuran derivative used in Europe for the treatment of peripheral venous disorders. Jaundice and serum alanine aminotransferase activity increased while drug administration was continued, but promptly decreased when it was eventually interrupted. Liver lesions were those of chronic active hepatitis. Anti-smooth muscle antibodies were present at a titer of 1:500 and disappeared 8 months after withdrawal of benzarone.
Alanine Transaminase↗
Prolonged cholestasis after troleandomycin-induced acute hepatitis.
We report the case of a patient in whom troleandomycin-induced hepatitis was followed by prolonged anicteric cholestasis. Jaundice occurred after administration of troleandomycin for 7 days and was associated with hypereosinophilia. Jaundice disappeared within 3 months but was followed by prolonged anicteric cholestasis marked by pruritus and high levels of alkaline phosphatase and gammaglutamyltransferase activities. Finally, pruritus disappeared within 19 months, and liver tests returned to normal 27 months after the onset of hepatitis. This observation demonstrates that prolonged cholestasis can follow troleandomycin-induced acute hepatitis.
Acute Disease↗
Prolonged cholestasis after cyproheptadine-induced acute hepatitis.
We report a patient in whom cyproheptadine-induced hepatitis was followed by prolonged cholestasis marked by elevation of serum alkaline phosphatase levels, gammaglutamyltransferase and bile acid levels, and disappearance of small bile ducts. Chlorpromazine and imipramine, which can induce a similar acute hepatitis followed by protracted cholestasis, have a close chemical structure (i.e., a tricyclic ring). We suggest that this structure might be involved in this type of hepatotoxicity.
Acute Disease↗
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↗
[Tricyclic structure of drugs and hepatotoxicity].
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Anticonvulsants↗
Inhibition of mitochondrial beta-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug.
Administration of pirprofen may produce microvesicular steatosis of the liver in humans. The effects of pirprofen on the mitochondrial beta-oxidation of fatty acids have been investigated in mice. In vitro, addition of 2 mM pirprofen decreased by 50% the formation of [14C]acid-soluble beta-oxidation products, and decreased by 70% the formation of [14C]CO2 upon incubation of hepatic mitochondria with [14C]palmitic acid, ATP, carnitine and coenzyme A. In vivo, administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before that of [U-14C]palmitic acid, decreased by 70% the exhalation of [14C]CO2 during the next 6 hr. Administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before the measurement, decreased plasma beta-hydroxybutyrate by 60%, plasma acetoacetate by 30% and blood glucose by 40%. Administration of pirprofen (2 mmol . kg-1 i.p.) 6 hr before sacrifice, doubled hepatic triglycerides content and produced microvesicular steatosis of the liver. We conclude that pirprofen inhibits the mitochondrial beta-oxidation of fatty acids in mice, thus explaining the microvesicular steatosis observed in mice and in some human subjects.
Animals↗
Formation of an inactive cytochrome P-450Fe(II)-metabolite complex after administration of amiodarone in rats, mice and hamsters.
Administration of amiodarone hydrochloride (50-150 mg/kg i.p. daily) to rats, mice or hamsters resulted in the in vivo formation of a cytochrome P-450Fe(II)-amiodarone metabolite complex absorbing at 453 nm, unable to bind CO and biologically inactive. In rats, the amount of complex present in hepatic microsomes was small 24 hr after administration of a single dose of amiodarone (100 mg/kg i.p.) but was increased 2.5-times by pretreatment with phenobarbital and 8-times by pretreatment with dexamethasone phosphate. In addition, the complex increased linearly with time as the doses of amiodarone were repeated daily. When both enhancing factors were combined (treatment for 3 days with both dexamethasone and amiodarone), the amount of complex present in liver microsomes reached 0.78 nmol/mg protein or 40% of total cytochrome P-450 in rats. In these rats, in vitro disruption of the complex with potassium ferricyanide suppressed its Soret peak at 453 nm, increased by 70% the CO-binding spectrum of dithionite-reduced microsomes, and restored several monooxygenase activities. The 453 nm-absorbing complex was also formed in vitro upon incubation of amiodarone or N-desethylamiodarone with NADPH, EDTA and microsomes from dexamethasone-treated rats. The formation of the complex was smaller with microsomes from phenobarbital-treated rats and was not detected with microsomes from control rats. We conclude that amiodarone forms an inactive cytochrome P-450Fe(II)-metabolite complex in rats, mice and hamsters.
Amiodarone↗
Prolonged cholestasis after ajmaline-induced acute hepatitis.
We report the cases of 3 patients in whom ajmaline-induced acute hepatitis was followed by anicteric cholestasis persisting for more than 1 year after cessation of administration of the drug. Ajmaline was given for 8-16 days before the onset of acute hepatitis. Jaundice was preceded by fever, chills and abdominal pain, and was associated with hypereosinophilia. The initial lesions included centrilobular cholestasis and portal inflammatory infiltration. Jaundice lasted for 3 weeks to 11 months. In these 3 patients liver tests were still abnormal 17-26 months after ajmaline withdrawal; histological examination, performed 9-26 months after the onset of jaundice, showed a decreased number of interlobular bile ducts, ductular proliferation, and mild portal fibrosis; circulating immune complexes were demonstrated. These observations demonstrate that prolonged cholestasis can follow ajmaline-induced acute hepatitis. Persistence of cholestasis long after the withdrawal of ajmaline suggests some form of autoimmunity.
Acute Disease↗
Cross hepatotoxicity between tricyclic antidepressants.
Cross hepatotoxicity between drugs in very uncommon. We report the case of a patient in whom acute hepatitis was induced by a tricyclic antidepressant, amineptine, and recurred early after administration of another tricyclic antidepressant, clomipramine. This observation suggests that the tricyclic ring is involved in the mechanism of the deleterious effect of both drugs to the liver.
Acute Disease↗
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↗
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↗