Environmental factors of enzyme induction and inhibition.
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Animals↗
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Accelerated elimination of pimonidazole following microsomal enzyme induction in mice: a possible approach to reduced neurotoxicity of the pimonidazole-etanidazole combination.
The pimonidazole-etanidazole combination shows promise for improved radiosensitization, although pimonidazole may increase the dose-limiting peripheral neurotoxicity of etanidazole in man. Induction of liver microsomal drug metabolizing enzymes by phenobarbitone resulted in reduced exposure to pimonidazole in plasma, brain, and tumor in mice. Peak tumor concentrations were lowered, but to a lesser extent. Phenobarbitone induction caused no change in the urinary ratio of pimonidazole to its N-oxide metabolite, and in fact, markedly reduced the circulating metabolite concentrations in plasma. There was no effect of phenobarbitone on plasma or tissue pharmacokinetics of etanidazole, which is eliminated by renal clearance. The results suggest that hepatic microsomal enzyme induction may be a possible approach to reducing the toxicity of the pimonidazole-etanidazole combination, and may also provide valuable information on the enzymology of pimonidazole metabolism.
Animals↗
Impact of neonatal benzpyrene imprinting on liver microsomal enzyme induction by benzpyrene and phenobarbital in adulthood.
A single neonatal treatment of rats with benzpyrene accounted for a durable induction of the liver microsomal enzyme (PSMO) system. Neonatal treatment with benzpyrene enhanced the inducing action of phenobarbital administrated in adulthood, but did not change the effect of benzpyrene treatment in the adult age. It follows that the imprinting and inducing effects of the neonatal benzpyrene treatment took different trends.
Animals↗
Iproclozide fulminant hepatitis. Possible role of enzyme induction.
The authors report the cases of 3 patients who died from fulminant hepatitis after receiving iproclozide, a hydrazine-containing monoamine oxidase inhibitor. Fulminant hepatitis in these patients resembled that reported in patients receiving other hydrazine-containing monoamine oxidase inhibitors: (1) the 3 patients were women; (2) the monoamine oxidase inhibitor has been ingested for 1 month or more; (3) the main clinical manifestations were jaundice and disorders of consciousness; (4) hypersensitivity manifestations were absent; (5) the predominant liver lesion was necrosis; (6) all 3 patients died. In our 3 patients, jaundice occurred 7 to 10 days after the adjunction to iproclozide of a microsomal enzyme inducer. These observations suggest that concomitant administration of iproclozide and of microsomal enzyme inducers may produce fulminant hepatitis in man. It is speculated that iproclozide could be, like iproniazid, transformed into a hepatotoxic metabolite, the production of which would be increased by microsomal enzyme induction.
Adult↗
[Enzyme induction by Epstein-Barr-virus-producing infection of lymphoblastoid cell lines].
By means of biological in vitro assay collagenolytic activity of normal peripheral lymphocytes was compared to that of EBV-infected lymphoblastoid cell lines: the EBV-producing P3HR1 cells and the non-productive Raji cells. While normal lymphocytes and Raji cells revealed only traces of activity, significantly increased (p less than 0.001) collagenolytic activity was detected in samples of P3HR1, the cell-free EBV-suspension alone showed no collagenolysis. The described enzymatic activity was fully inhibited by 0-phenanthroline and EDTA indicating collagenase action. As main explanations for the phenomenon we suggest the possibility of viral enzyme induction, increased release of protease and thirdly that EBV carries a gene for synthesis of a collagenase.
Burkitt Lymphoma↗
Differences in hepatic drug accumulation and enzyme induction after chronic amiodarone feeding of two rat strains: role of the hydroxylator phenotype?
1. It has previously been shown that the extent of hepatic phospholipidosis induced by chronic amiodarone treatment correlates with the degree of drug accumulation in liver tissue. 2. To investigate a possible influence of pharmacogenetic factors, biochemical and morphological investigations were carried out in two rat strains differing in debrisoquine hydroxylation. 3. Plasma and liver tissue concentrations of amiodarone and its main metabolite, desethyl-amiodarone, were significantly higher in rats with deficient hydroxylation. Microsomal enzyme induction, drug cytochrome P-450 complex formation and typical ultrastructural features of phospholipidosis were only seen in rats with deficient hydroxylation and in a more sensitive species, the guinea-pig. 4. It remains to be seen whether deficient debrisoquine hydroxylation in man is associated with an increased susceptibility to amiodarone side effects.
Amiodarone↗
The myasthenic (Eaton-Lambert) syndrome associated with carcinoma. Enzyme induction as a possible mechanism of paraneoplastic syndromes.
A myasthenic syndrome associated with small-cell tumours of the bronchus and with autoimmune diseases (Eaton-Lambert syndrome) has been attributed to diminished probability that a nerve action potential will release acetylcholine (ACh) from terminals of cholinergic nerves (somatic motor and autonomic). This model derives from evidence for reduced quantal content of the transmitter released by a nerve impulse. The test procedure implies certain constancies of postsynaptic response. Abnormal responses to ACh-agonists indicate that receptor response is not normal. It is suggested that all previously described neuromuscular responses are compatible with new model: the subsynaptic apparatus produces excess acetylcholinesterase (AChE) which limits the endplate conductance changes produced by normal output of ACh. This model is supported by earlier ultramicroscopic studies which cannot be accounted for by the contemporary model. It is proposed that enzyme induction by peptide or immunoglobulin may also be responsible for other paraneoplastic syndromes.
Acetylcholine↗
Bioavailability of hetacillin in rats after liver enzyme induction by various inducers with or without protein binding properties.
The serum levels and the half life of ampicillin derived from Hetacillin after administration of the latter to a total of 61 rats classified in 7 groups were determined. Each of these groups was pre-treated for 15 days with the following inducers; phenobarbital, diphenylhydantoin, diazepam, chlorpromazine and phenylbutazone. The control group received saline. The d-glucaric acid concentration in the urine prior to and after the administration of inducers and the liver weight were taken as enzyme induction indices. Results showed a positive correlation between the indices of induction and the levels of ampicillin originating from hetacillin with a significant correlation coefficient between the serum levels of ampicillin and urine d-glucaric acid for all drugs studied. The different effect of the various drugs indicated that they could be classified into the following two groups: a) those that induced a significant increase of the levels and half life (t1/2) of ampicillin. The effect was significant in decreasing order for phenylbutazone (r = 0,990), diazepam (r = 0,990) and diphenylhydantoin (r = 0,753). b) those which initially resulted in a significant increase of the levels of ampicillin and thereafter in a decrease with a significant shortening of its t1/2 too. The effect was most significant for phenobarbital (r = 0,887) and less so for chlorpromazine (r = 0,800). Only for these two drugs was a significant and actually negative correlation observed between d-glucaric acid and t1/2 that is: phenobarbital (r = -0,967) chlorpromazine (r = -0,752). Results suggest an interaction of Hetacillin and the above inducers.
Ampicillin↗
Influence of liver enzyme induction caused by diphenylhydantoin and diazepam on bone mass of rats.
25 albino rats of Wistar strain were used for the study. They were divided into three groups. Animals of the first group (n = 10) were treated with Diphenylhydantoin in a daily dose of 70 mg/kg for three months. Animals of the second group (n = 10) were treated with Diazepam in a daily dose of 10 mg/kg for 3 months. Animals of the third group (n = 5) were treated with 5% acacia oil for the same period of time. Food and water consumption together with motor activity were measured. As indices of enzyme induction, D-Glucaric acid and liver weight were determined. Also the following bone indices were determined: femur Ca/femur weight, femur Ca/body weight, humerus Ca/humerus weight, humerus Ca/body weight, femur specific weight, humerus specific weight. Statistically significant alterations of bone mass were found.
Animals↗
Barbiturate-induced choleresis: possible independence from microsomal enzyme induction.
The influence of four barbiturates, phenobarbital, barbital, thiopental, and pentobarbital, on bile secretion and on the hepatic microsomal system was studied in anesthetized rats. The barbiturates were injected intraperitoneally for 4 days and the animals were studied on the 5th day. It was found that: (1) phenobarbital, barbital, and thiopental, but not pentobarbital, significantly increased liver weight, cytochrome P-450 concentration in the liver, decreased pentobarbital sleeping time and induced a hypertrophy of the smooth endoplasmic reticulum in the hepatocytes at electron microscopy; (2) in contrast, the four barbiturates, including pentobarbital, significantly increased bile flow; this increase was attributed to an increase in the bile acid independent bile flow. There was no correlation between the increase in bile flow and the cytochrome P-450 concentration in the liver. It is concluded that the increase in bile flow observed after barbiturate treatment in the rat is possibly independent of the hepatic microsomal enzyme induction produced by these drugs.
Animals↗
Relationship between dicumarol distribution and the effect of enzyme induction on dicumarol elimination in rats.
Pronounced intersubject differences in the apparent first-order elimination rate constant (kapp) for dicumarol in rats have been found to be due to corresponding differences in the distribution of dicumarol between the liver (the site of dicumarol biotransformation) and the rest of the body. From theoretical considerations and experimental results in animals given only dicumarol, it has been shown that kapp is linearly related to the fraction of drug in the liver (FL). The proportionality constant (k) for these variables was defined as the intrinsic elimination rate constant for dicumarol which should reflect the activity of the enzyme system(s) involved in the elimination of this drug. The purpose of this investigation was to determine the effect of enzyme induction on dicumarol distribution and on the relationship between kapp and FL in rats. It was found that pretreatment with phenobarbital caused a substantial increase in kapp, but that it had no apparent effect on the serum/liver and serum/kidney concentration ratios of dicumarol. The relative weight of the liver was significantly increased by phenobarbital treatment but the weight of the kidneys was not affected. Linear relationships between kapp and FL were found for both the control and the phenobarbital treated groups, but with a significant difference in the slopes of the regression lines. This study illustrates the application of a pharmacokinetic technique which permits a clear and quantitative distinction between the relative contributions of enzyme activity and body distribution to the in vivo elimination kinetics of a drug.
Animals↗
Biphasic response for hepatic microsomal enzyme induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice.
The induction of the murine hepatic microsomal cytochrome P-450 monooxygenase system by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied over a wide range of doses, including those associated with acute toxicity. Studies were conducted in two inbred strains of mice which vary at the Ah receptor and at a number of other genetic loci. C57BL/6J mice possess a high-affinity Ah receptor and are responsive to enzyme inductive effects of TCDD, whereas DBA/2J mice do not possess a high-affinity receptor and are less responsive to TCDD. In a dose-response study, 7-ethoxyresorufin O-deethylase (EROD) activity appeared to be maximally induced in C57BL/6J and DBA/2J mice at 7 days following exposure to 3 and 30 micrograms of TCDD/kg respectively. Very similar results were reported previously for the induction of aryl hydrocarbon hydroxylase activity in these strains of mice. However, at higher doses of TCDD (at least 45 micrograms/kg for C57BL/6J and 300 micrograms/kg for DBA/2J), EROD activity was further increased (2-fold) from the apparent maximal (plateau) level, resulting in an unusual biphasic log dose-response relationship. EROD activity remained at these elevated rates in both strains for doses approaching and exceeding the respective LD50 values for each strain. To further characterize this biphasic induction phenomenon, cytochrome P-450 content, benzo[a]pyrene metabolism, and EROD and NADPH-cytochrome P-450 reductase activities were measured 1, 3 and 7 days after TCDD administration to C57BL/6J (3 and 150 micrograms/kg) and DBA/2J (30 and 600 micrograms/kg) mice. Maximal responses occurred in both strains at 3 days for all doses. In both strains, TCDD produced a dose-dependent increase in cytochrome P-450 content, EROD, and benzo[a]pyrene metabolism. Furthermore, a 2-fold induction of reductase activity was observed in each strain following exposure to the respective high doses. Induction of cytochrome P1-450 and P3-450 was also measured by Western immunoblot, using antisera raised against the homologous rat isozymes. In both strains, TCDD produced a dose-related increase in two protein-staining bands recognized by anti-P-450BNF-B (P1-450) and anti-P-450BNF/ISF-G (P3-450) respectively. The extended induction of hepatic microsomal monooxygenase activities at the respective high doses of TCDD appears to be due, in part, to increases in NADPH-cytochrome P-450 reductase activity and cytochromes P1-450 and P3-450 content. Significant alterations in the expression of the cytochrome P-450 monooxygenase system following exposure to high doses of TCDD may be associated, in part, with the delayed acute toxicity reported at this level of exposure.
Aminopyrine N-Demethylase↗
Hepatic enzyme induction and leucocyte delta-aminolaevulinic acid synthase activity: studies with carbamazepine.
Antipyrine metabolism, daily urinary 6-beta-hydroxycortisol excretion, carbamazepine (CBZ) half-lives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half-lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose-dependent hetero- and auto-inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.
5-Aminolevulinate Synthetase↗
Urinary 6beta-hydroxycortisol/17-hydroxycorticosteroids ratio as a measure of hepatic CYP3A4 capacity after enzyme induction.
BACKGROUND: The correlation between the urinary 6beta-hydroxycortisol/17-hydroxycorticosteroids (6beta-OHF/17-OHCS) ratio and the metabolic capacity of the most abundant form of hepatic cytochrome P450 (CYP3A4) after induction remains unclear. METHODS: Concentrations of 6beta-OHF and 17-OHCS in spot urine specimens obtained from 61 epileptic children receiving continuous carbamazepine therapy were measured by high-performance liquid chromatography. The relationship between the urinary 6beta-OHF/17-OHCS ratio and the serum carbamazepine concentration, corrected for dose and body weight, was examined. RESULTS: Serum carbamazepine was inversely associated with the urinary 6beta-OHF/17-OHCS ratio, and the hyperbolic relationship between the two parameters was statistically significant (P < 0.01). DISCUSSION: Carbamazepine is well known as a potent inducer and a substrate of hepatic CYP3A4. The present results suggest that measurement of the urinary 6betaOHF/17-OHCS ratio is helpful for assessing individuals' hepatic CYP3A4 capacity after enzyme induction.
17-Hydroxycorticosteroids↗
Enzyme induction in cryopreserved human hepatocyte cultures.
Freshly isolated human hepatocytes are considered as the gold standard for in vitro testing of drug candidates. Meanwhile also cryopreserved human hepatocyte suspensions are available. However, a drawback of these cells is the incalculability of attachment to the culture dish. Therefore, we established a technique freezing hepatocytes cultured on a collagen gel. After thawing damaged cells were removed to a certain extent by gentle washing with culture medium prior to adding an upper gel layer. The morphology of the resulting hepatocyte cultures could not be distinguished from that of non-frozen cells. However, basal activities of cytochrome P450 isoforms decreased in cryopreserved compared to non-frozen hepatocytes, as evidenced by analysis of testosterone hydroxylation (OHT) in positions 6beta, 16alpha, 2beta and 6alpha. Nevertheless, enzyme induction factors caused by 24 h incubation with 50 microM rifampicin were similar in cryopreserved and non-frozen hepatocytes. In cryopreserved hepatocytes rifampicin caused an increase in mean values of 6beta-OHT formation from 57.2 to 157.7 pmol/well/min (2.8-fold), compared to an increase from 115.8 to 269.1 pmol/well/min (2.3-fold) in non-frozen cells. Similarly, 16alpha- and 2beta-OHT showed induction factors of 2.4- and 2.3-fold in cryopreserved compared to 1.6- and 2.4-fold in non-frozen hepatocytes, respectively. In conclusion, human hepatocytes cryopreserved on collagen gels show a clear induction of CYP3A4 by rifampicin, although the basal activities are reduced compared to non-frozen cells.
Aged↗
Further observations on effects of cations on enzyme induction in marine bacteria.
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Bacteria↗
Rapid reversal of ethionine inhibition of enzyme induction in Pseudomonas aeruginosa by L- and D-methionine.
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Enzyme Induction↗
Physiological responses of bacteria to cytochalasin A: effects on growth, transport, and enzyme induction.
Cytochalasin A at 5 to 25 microgram/ml (1.0 x 10(-5) to 5.2 x 10(-5) M) inhibited the growth of three gram-positive bacteria, Arthrobacter sialophilus, Staphyloccus aureus, and Bacillus amyloliquifaciens, but had little or no effect on the growth of three gram-negative bacteria, Excherichia coli, Pseudomonas maltophilia, and Aeromonas proteolytica. A. sialophilus and S. aureus recovered spontaneously from cytochalasin A-mediated growth inhibition after a considerable lag period, which was dependent on the drug dose. It was demonstrated that this long-term recovery did not involve selection of resistant variants. Cytochalasin A had no detrimental effect on cell viability in A. sialophilus or S. aureus, but caused lysis of B. amyloliquifaciens. The drug prevented enzyme inductions and inhibited transport of valine, uridine, and glucose in the gram-positive organisms. It had little or no effect on these processes in the gram-negative organisms. In studies with A. sialophilus, the drug inhbitied respiration of exogenous substrates, but did not depress endogenous respiration. These results constitute the first unequivocal evidence for the bacteriostatic properties of this class of compounds and indicate that cytochalasin A halts various physiological processes in gram-positive bacteria primarily by inhibiting solute transport.
Bacteria↗