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PubMed1986

Polychlorinated dibenzo-p-dioxins: quantitative in vitro and in vivo structure-activity relationships.

There were marked effects of structure on the activities of 14 polychlorinated dibenzo-p-dioxins (PCDDs) as competitive ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor and as inducers of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells in culture. 2,3,7,8-TCDD was the most active compound in both assays and several PCDD congeners which were fully substituted in the lateral 2, 3, 7 and 8 positions but also contained additional chlorosubstituents in non-lateral 1, 4, 6 and 9 positions were less active. It was also evident that there was a decrease in in vitro binding and induction activities with decreasing lateral chlorine substitution. Although comparable structure-activity relationships (SARs) for the PCDDs were observed for the induction and receptor binding assays, there was not a linear or rank order correlation between the 2 sets of data. Several in vivo biologic and toxic activities of 2,3,7-trichloro-, 2,3,7,8- and 1,3,7,8-tetrachloro-, 1,2,4,7,8- and 1,2,3,7,8-pentachloro- and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin were determined in a dose-response fashion in immature male Wistar rats. The ED50 values for hepatic microsomal AHH and EROD induction, body weight loss and thymic atrophy were obtained. There was an excellent linear correlation between the -log EC50 values for AHH or EROD induction in cell culture and the -log ED50 values for enzyme induction, body weight loss and thymic atrophy in the rat. The in vitro enzyme induction data could be used to quantitatively estimate the toxicity of the PCDD congeners in the rat: this latter correlation has previously been observed for a series of polychlorinated dibenzofurans.

Animals↗
PubMed1976

Role of the hypophysis in estrogen-mediated induction of enzymes in the regenerating liver from castrated male rats.

Perfusions with corticosterone, of isolated regenerated livers from adult male rats, subjected to castration, partial hepatectomy and hypophysectomy with or without estradiol treatment during parenchymal regeneration, yielded very similar patterns of biliary steroid metabolites. The degree of steroid conjugation was lower than that seen in livers from normal, untreated, adult male rats. In operated animals, with or without estradiol benzoate treatment, ring A-reduced 20-keto metabolites constituted about 20%, whereas metabolites with a 20-hydroxy group made up approximately 80% of the corticosterone metabolites formed. Furthermore, no 15-hydroxylated metabolites derived from corticosterone, quantitatively the most important compounds in bile from female rats, could be detected in bile from these treated male animals. However, livers from male rats which had been castrated, hepatectomized and treated with estradiol benzoate during liver regeneration, produced 15-hydroxy-tetrahydrocorticosterone to the same extent as female rat livers, when perfused with corticosterone. The results obtained indicate that the effects of estradiol on the induction and differentiation of steroid metabolizing enzymes in the regenerating liver are pronounced and manifested only in the presence of an intact hypophysis.

Animals↗
PubMed1976

Metabolic activation of aromatic hydrocarbons in purified rat liver nuclei: induction of enzyme activities and binding to DNA with and without monooxygenase-catalyzed formation of active oxygen.

Purified rat liver nuclei covalently bound low levels of seven aromatic [14C]hydrocarbons to nuclear DNA. Induction with 3-methylcholanthrene increased the binding of six carcinogenic hydorcarbons, but did not raise the level of binding of noncarcinogenic anthracence. Removal of the nuclear envelope by Triton N-101 eliminated binding and aryl hydrocarbon hydroxylase activities and cytochrome P-450 from the nuclei. Binding of two of two strong carcinogens, benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene, to nuclear DNA was compared to the levels of aryl hydrocarbon hydroxylase and cytochrome P-450 in nuclei from uninduced and benz[a]anthracene-, 3-methylcholanthrene-, and phenobarbital-induced rats. Microsomal hydroxylase and cytochrome P-450 were also assayed. Induction with 3-methylcholanthrene gave the largest increases in nuclear activities: 11 times as much hydroxylase, 6 times as much cytochrome P-450, and 4 times as much binding of both hydrocarbons. Benz[a]anthracene and phenobarbital induced these nuclear activities 0- to 4-fold. In the presence of added NADPH, binding of benzol[a]pyrene to DNA by nuclei increased rapidly for at least 20 min. When NADPH was not added, the reaction stopped at a low level in 5 min. When CO was bubbled through the reaction mixture with or without added NADPH, binding of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene was partially inhibited, indicating that cytochrome P-450 plays a role in this activation. Since no nuclear hydroxylase activity was seen without added NADPH or in the presence of CO, activation and subsequent binding of hydrocarbons to nuclear DNA, at least in part, does not require the activated oxygen used in monooxygenase reactions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Evidence for two control genes regulating expression of the quinic acid utilization (qut) gene cluster in Aspergillus nidulans.

The first three steps in quinic acid degradation in Aspergillus nidulans are catalysed by highly inducible enzymes encoded by a gene cluster regulated by an adjacent control region. Analysis of two non-inducible mutants has been done in diploid strains, where qutA8 is recessive and all three enzyme activities are fully induced in heterozygous qutA8/qutA+ diploids. In contrast, qutA4/qutA+ heterozygous diploids show semi-dominance of the mutant allele, giving markedly diminished growth on quinic acid and 30-40% decrease of enzyme induction. Strikingly, the qutA4/qutA8 heterozygous diploid grows to the same degree on quinic acid as the qutA4/qutA+ heterozygote and shows the same level of enzyme induction, whereas both the homozygous mutant diploids do not grow on quinic acid and show no enzyme induction. Therefore the two mutant genomes complement, identifying two distinct regulatory gene functions. A genetic model is proposed of a negatively acting gene (qutA) repressing expression of a positively acting gene (qutD, previously designated qutA8+) whose product is in turn required for expression of the three structural genes. The qutA4 mutation is interpreted to produce an altered repressor insensitive to quinic acid, and the qutD8 mutation the loss of activator protein. Close similarity in the regulation of the quinic acid gene cluster in Neurospora crassa suggests that the two types of control mutation, qalS and qalF, described for N. crassa may also reflect two regulatory genes.

Alcohol Oxidoreductases↗
PubMedDate not supplied

[Effect of induction of enzymes of the cytochrome p-450 system on the survival of rats after acute hemorrhage].

The effect of acute hemorrhage on the functional status of microsomal cytochrome P-450-dependent hepatic monoxygenases and the impact of induction of these monoxygenases on the survival of posthemorrhagic male Wistar rats. Acute blood loss of the rats, which caused 50% deaths led approximately to a double decrease in the hepatic activity of 77-ethoxycoumarin-O-deethylase (ECOD). Induction of hepatic monoxygenases by phenobarbital in a dose of 80 mg/kg for 3 days, which caused a 2.4-fold increase in the activity of ECOD as compared with the controls, prolonged the survival rate of posthemorrhagic rats from 50 to 85%.

Acute Disease↗
PubMed1998

Subchronic toxicity studies of sucrose acetate isobutyrate (SAIB) in the rat and dog.

Preliminary short-term toxicity studies of sucrose acetate isobutyrate (SAIB) in the dog demonstrated that addition of this additive to the diet was associated with an increase in liver size and elevated serum alkaline phosphatase activity with no evidence of pathological change by light microscopy. To determine the basis for these changes, a 12-week oral toxicity study of SAIB was conducted in the dog and a similar study was performed in the rat. SAIB was fed in the diet to groups of six beagle dogs of each sex at 0, 0.5, 1.0, 2.0 and 4.0%. SAIB was also fed to groups of 40 Sprague-Dawley rats of each sex at levels of 0, 2.5, 5.0 and 10.0%. In the rat study, in addition to routine toxicology parameters, hepatic microsomal enzyme induction was determined using a zoxazolamine hypnotic test, urinary ascorbic acid excretion and determination of hepatic carboxylesterase activity. Sodium phenobarbital was fed to groups of 20 rats of each sex at a dose of 100 mg/kg body weight/day by gavage as a positive control for hepatic microsomal enzyme induction. In the dog study, routine toxicological tests were supplemented by tests for bromsulfophthalein (BSP) retention, histochemical staining of liver sections for glycogen, phosphorylase, succinate dehydrogenase, and acid and alkaline phosphatases. Levels of liver lipid, protein, glycogen and carboxylesterase activity were also determined. Electron microscopic examinations were made on liver sections from the dog study at the end of the 12-week SAIB feeding period and after a 2-week withdrawal period. Administration of SAIB to rats did not reveal evidence of any effect on hepatobiliary function, and there was no indication of microsomal enzyme induction. Body weight gain of male rats fed SAIB was decreased, probably as the result of decreased palatability of the diet; SAIB did not affect body weight gain in females. The changes observed in the dogs fed SAIB included increased serum alkaline phosphatase activity with no change in serum alanine aminotransferase, aspartate aminotransferase or lactic dehydrogenase activity and no change in serum electrolyte, serum protein, glucose or bilirubin levels. No haematological changes were observed. BSP retention was observed at all SAIB dose levels. There were no SAIB-related pathological changes in any organ when examined by light microscopy. Examination by electron microscope revealed dilatation of bile canaliculi and an increase in smooth endoplasmic reticulum compared with controls. Histochemical studies also indicated increased enzyme activity of the bile canaliculi. The electron-microscope-revealed changes were completely reversed during a 2-week treatment withdrawal period. The dog study did not establish a no-effect level for changes in hepatobiliary function induced by feeding SAIB.

Alkaline Phosphatase↗
PubMed1981

Genetic differences in reductive metabolism and hepatotoxicity of halothane in three rat strains.

The relationship between the reductive metabolism of halothane and hepatotoxicity was examined in three rat strains (Fischer 344, Sprague-Dawley, and black hooded Wistar) to determine if there were genetic differences in 1) the reductive metabolism of halothane under identical exposure conditions, and 2) the susceptibility to the hepatotoxic effects of halothane. Halothane hepatotoxic was produced in all rat strains by exposing phenobarbital-pretreated rats to 1 per cent halothane under mild hypoxia (14 per cent oxygen, inspired) for 2 h. Generally the levels of both 2-chloro-1,1,1-trifluoroethane (CTF) and 2-chloro-1,1-difluoroethylene (CDF), two volatile metabolites of halothane, increased from the onset of anesthetic exposure and reached a plateau after approximately 60 min. The exception to this trend were phenobarbital-pretreated Wistar rats (exposed to 1 per cent halothane with 14 per cent oxygen) where the levels of either CDF or CTF were high initially (10-min sample) and decreased in subsequent samples to reach a plateau after 80 min. The plateau levels of both CDF (approximately 6 ppm) and CTF (approximately 20 ppm) were not significantly different among the three rat strains exposed to halothane (1 per cent) and hypoxia with prior enzyme induction. There were, however, significant differences in both biochemical and pathological changes among the three strains exposed under the above identical conditions when the rats were killed 24 h after anesthetic exposure. For example, serum alanine aminotransferase (ALT) was increased fourfold in the Fischer strain but only doubled for the other two strains. Moreover, while all three strains had various amounts of hepatocyte damage in the vicinity of the central veins when the rats were exposed to halothane, hypoxia, and enzyme induction, only the Fischer strain showed hepatocyte damage under the exposure conditions of halothane (1 per cent) and normoxia (21 per cent oxygen, inspired) with prior enzyme induction. The results support the role of reductive metabolism of halothane in the etiology of halothane hepatotoxicity. Furthermore, they suggest that genetic variations in the susceptibility of the liver to the reactive intermediates or metabolites formed during reductive metabolism of halothane may be a significant factor in halothane hepatotoxicity.

Alanine Transaminase↗
PubMed1983

The role of microsomal enzyme inducers in the reduction of misonidazole neurotoxicity.

In a series of studies, we have shown that phenytoin, 300 mg daily for one week, produces consistent hepatic microsomal enzyme induction, resulting in a decrease of 25% in misonidazole half-life, without causing any toxicity per se. A longer period of administration gives only a slightly greater induction. Phenobarbitone in a daily dose of 90 mg causes a reduction of 18% and 23% in misonidazole half-life after 1 and 2 weeks' pre-treatment respectively, but is less suitable clinically because of its sedative effect. A further series of studies using phenytoin as the inducing agent has shown that, despite adequate enzyme induction and increased misonidazole metabolism, it is impossible to increase the total dose of misonidazole beyond the usually accepted value of 12 g/m2 because of unacceptable neuropathy (a rate of 50% at a dose of 14 g/m2 over three weeks). In single doses of above 3.0-4.0 g of misonidazole, severe nausea and vomiting are prominent, so that this side effect is a determining factor in the treatment fractionation. Audiometric studies show no correlation between the incidence of peripheral neuropathy and abnormal audiograms, and have no value in the early prediction of neurotoxicity. It seems that despite causing increased metabolism, enzyme induction does not protect against neurotoxicity and thus will not permit the use of higher doses of misonidazole for increased radiosensitisation.

Adult↗
PubMed1986

Influence of phenobarbital on the hepatic handling of [3H]vitamin D3 in the dog.

The effect of phenobarbital (PB) on the hepatic handling of vitamin D3 (D3) and its metabolism to 25-hydroxyvitamin D3 [25(OH)D3] was studied in eight mongrel dogs. The hepatic uptake and clearance of [3H]D3 were evaluated by the multiple indicator-dilution curve technique, and the formation of [3H]25(OH)D3 was evaluated by sampling the hepatic effluent. The hepatic enzyme induction was assessed in six dogs by the 14CO2 breath excretion test. The results show that the hepatic uptake of [3H]D3 was not significantly affected but that its hepatic clearance was significantly increased during PB treatment. The [3H]25(OH)D3 production was increased during PB administration by a factor of 3-5 times over the pre- or post-PB period. Evaluation of the enzyme induction produced by PB revealed that two of the dogs studied had a blunted response to PB; furthermore, these dogs were the only animals that showed no increase in [3H]25(OH)D3 production during PB treatment and that in the presence of similar serum PB, endogenous 25(OH)D3 and 1,25-dihydroxyvitamin D3 pools, and hepatic uptake and clearance of [3H]D3. Strong positive correlation coefficients were observed between the breath excretion of 14CO2 and the [3H]25(OH)D3 production during PB treatment, whereas no correlation was present in the absence of PB. These observations show that, in most animals, PB is accompanied by an increased hepatic clearance of [3H]D3 and by an increased production of [3H]25(OH)D3. The data obtained during the present study also show that the response to PB is heterogeneous and that some animals escaped PB-mediated enzyme induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyrine↗
PubMed1976

The effect of phenobarbital on cyclophosphamide antitumor activity.

We have used the spleen colony assay system and survival duration studies in male DBA/2 mice with P388 leukemia to study the effects of microsomal enzyme induction by phenobarbital on the antileukemic activity and bone marrow toxicity of cyclophosphamide. Phenobarbital drinking water (0.5 mg/ml) was given for 7 days prior to cyclophosphamide (10 to 200 mg/kg i.p.). Average daily phenobarbital intake per mouse was 1.25 mg (equivalent to 4 mg/kg/day human dosage). Dose-response curves with and without phenobarbital pretreatment showed a constant 90% (1-log) reduction in the toxicity of cyclophosphamide to leukemic colony-forming units, whereas enzyme induction had no effect on the toxicity of the drug to normal bone marrow colony-forming units. Parallel survival studies confirmed the 1-log diminution in the antileukemic activity of cyclophosphamide in phenobarbital-pretreated mice. This phenobarbital-induced change in the antitumor activity of cyclophosphamide appears explainable on a pharmacokinetic basis. The Friedman and Boger assay for plasma alkylating metabolites showed that the reduction in the area under the plasma metabolite curve caused by enzyme induction exactly predicted the observed reduction in cyclophosphamide antitumor effect.

Animals↗
PubMed1992

Effects of nutrients and hormones on gene expression of ATP citrate-lyase in rat liver.

Northern-blot analyses demonstrated a strong gene expression of ATp citrate-lyase in liver and adipose tissue of rat and a weak expression in brain, heart, small intestine and muscle. After refeeding a carbohydrate/protein diet to fasted rats, the transcriptional rate had already increased within 2 h, the mRNA concentration reached a maximal level of approximately 30-fold increased in 16 h, and the enzyme induction increased sixfold in 48 h. By feeding only carbohydrate without protein, the transcriptional rate was increased threefold, and the mRNA concentration and enzyme induction comparably, to the levels in the carbohydrate/protein diet. It appears that protein feeding is not necessary to induce ATP citrate-lyase. In diabetic rats fed on a glucose diet, the transcriptional rate, mRNA concentration and enzyme level were very low in comparison with the normal. By fructose feeding, however, the transcriptional rate was more greatly increased and the mRNA concentration increased comparably to the levels reached by insulin treatment, while the enzyme induction was not so increased. Thus, it is suggested that insulin is important in regulated translation in addition to transcription. However, triiodothyronine treatment did not have much effect on the gene expression. As a result of the present experiment, it is noted that ATP citrate-lyase-gene expression was greatly dependent on carbohydrate.

ATP Citrate (pro-S)-Lyase↗
PubMed1983

Human tolerance of flumecinol (Zixoryn, RGH-3332), its regime and dosage in healthy volunteers.

The enzyme inductive effect of flumecinol (Zixoryn, RGH-3332), a new hepatic enzyme inducer, was studied in healthy volunteers. The dosages employed were as follows: 25, 50, 100, 200, 400, 600 and 800 mg single doses; and during a 7-day period single doses of 50 mg daily, and doses of 200, 300 and 400 mg three times daily. The intensity of enzyme induction was measured by the following parameters: antipyrine metabolic clearance, D-glucaric acid excretion, menthol loading, and total serum bilirubin. The minimal and optimal inductive doses of flumecinol were determined. A single dose of 600 mg of flumecinol is recommended at intervals of 7 days. This dosage also induces the first and the second phases of reactions. The induction effect becomes manifest after 24 hours. Its peak is reached between 48 and 96 hours, and the inductive activity ceases between 216 and 408 hours.

Adult↗
PubMed1977

Induction of placental alkaline phosphatase in choriocarcinoma cells by 5-bromo-2'-deoxyuridine.

Growth of choriocarcinoma cells in the presence of 5-bromo-2'-deoxyuridine (BrdUrd) results in a 30- to 40-fold increase in alkaline phosphatase activity. The effects of BrdUrd is specific for phosphatase with an alkaline pH optimum. The induction by BrdUrd is probably not due to the production of an altered enzyme, since the induced enzyme resembles the basal enzyme in thermal denaturation and kinetic properties. Enzyme induction can be prevented by thymidine but not by deoxycytidine or deoxyuridine. The induction of alkaline phosphatase appears to require incorporation of the BrdUrd into cellular DNA. The presence of BrdUrd in the growth medium is not necessary for alkaline phosphatase induction in proliferating cells containing BrdUrd-substituted genomes. However, enzyme induction and maintenance of the induced levels of alkaline phosphatase in nonproliferating cells containing BrdUrd-substituted DNA requires the presence of the analogues in the medium. The induction of alkaline phosphatase by BrdUrd in probably an indirect process.

Alkaline Phosphatase↗
PubMed1984

A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients.

The antipyrine clearance and the urinary excretion of D-glucaric acid (D-GA) were determined in 122 patients receiving chronic anticonvulsant drug treatment and in 21 drug-free control subjects. Patients treated with carbamazepine (CBZ), phenytoin (DPH), primidone (PMD) and phenobarbitone (PB), either alone or in combination, showed higher values of antipyrine clearance and excreted larger amounts of D-GA as compared to controls. While antipyrine clearance values did not differ significantly from one drug group to another, D-GA excretion was significantly higher in patients treated with CBZ than in those treated with DPH. In patients treated with sodium valproate antipyrine clearance did not differ from control values. There was a trend for D-GA excretion to be higher in these patients but the difference was not statistically significant. Significant positive correlations were found between the dosage of CBZ, DPH, PMD and PB and both indices of enzyme induction. These data demonstrate a dose-dependent degree of enzyme induction in patients receiving therapeutic doses of these anticonvulsants. The relative potency at average dose levels for antipyrine clearance was PB (1), DPH (0.92), CBZ (0.84), PMD (0.82) and for log D-GA excretion was PB (1), CBZ (0.96), PMD (0.95), DPH (0.90).

Anticonvulsants↗
PubMed1992

Degradation of chlorotoluenes by in vivo constructed hybrid strains: problems of enzyme specificity, induction and prevention of meta-pathway.

The activities of the TOL plasmid-coded xylene oxygenase, benzylalcohol dehydrogenase, benzaldehyde dehydrogenase of Pseudomonas putida strain PaW1 were tested with substituted toluenes, benzylalcohols and benzaldehydes, respectively, as substrates. Several chlorinated toluenes were shown to induce enzymes of the xylene degradation sequence. Conjugative transfer of the TOL plasmid from Pseudomonas putida strain PaW1 to Pseudomonas sp. strain B13 and Pseudomonas cepacia strain JH230 allowed the isolation of hybrid strains capable of growing in the presence of 3-chloro-, 4-chloro- and 3,5-dichlorotoluene. Hybrid strains revealed new ways to prevent the dead-end meta-pathway for cholorocatechols.

Alcohol Oxidoreductases↗
PubMed1997

Induction and inhibition of mouse cytochrome P-450 2B enzymes by musk xylene.

Musk xylene (MX) (1,3,5-trinitro-2-t-butylxylene) is a nitromusk perfume ingredient that although uniformly negative in a battery of genotoxicity tests, produces a high incidence of liver tumors in mice. The purpose of this work was to characterize the profile and dose-response relationship of microsomal enzyme induction following exposure to MX. MX was dosed by gavage to male B6C3F1 mice for 7 days at 0, 1, 5, 10, 20, 50, 100, and 200 mg/kg after which microsomes were prepared. At 200 mg/kg, MX increased liver weight by about 65% and increased microsomal cytochrome P-450 content 2-fold over control. MX increased microsomal activity for O-dealkylation of 7-ethoxy and 7-methoxyresorufin 4- and 2-fold, respectively, and increased the N-demethylation of erythromycin approximately 2-fold. These results were generally consistent with increased CYP1A1, 1A2, and 3A protein levels determined by Western blotting. In contrast, whereas no increase in O-dealkylation of 7-pentoxyresorufin (PROD) was observed, MX treatment increased CYP2B protein levels about 25-fold over control at 200 mg/kg. Furthermore, a single dosage of MX (200 mg/kg) increased Cyp2b-10 mRNA to a maximal level and with a time course similar to phenobarbital (PB). To study inhibition of CYP2B enzymes in vivo, mice were treated with PB (0.05% in drinking water for 5 days), then given a single dosage of corn oil or MX (200 mg/kg) at 2 or 18 hr before necropsy. PB treatment increased PROD activity 25-fold, and at 2 hr after MX treatment (associated with peak plasma levels of MX), there was no change in the PB-induced PROD activity. However, at 18 hr, MX treatment decreased PROD activity by 90%. Despite the in vivo inhibition, in vitro studies indicated that MX did not cause mechanism-based inactivation of CYP2B enzymes. The potential for nitroreduction of MX (catalyzed by anaerobic intestinal bacteria) to contribute to the inhibition of CYP2B enzyme activity was evaluated in a separate group of PB-induced mice that were dosed orally with a regimen of broad spectrum antibiotics (neomycin, tetracyline, and bacitracin) to reduce gut flora prior to administration of MX. In these animals, MX (200 mg/kg) did not inhibit PB-induced PROD activity. In summary, MX treatment produced general hepatic changes consistent with induction of CYP2B enzymes in mice and caused a large increase in CYP2B protein and mRNA levels. These data indicate that MX is a PB-like inducer of cytochrome P-450 enzymes and may cause liver tumors in a manner analogous to PB. However, no increase in CYP2B enzyme activity was observed, suggesting that MX or metabolites of MX also inhibit this enzyme. When the intestinal flora was eliminated by antibiotic treatment, MX no longer inhibited the CYP2B enzyme, indicating that anaerobic bacteria are capable of metabolizing MX, and suggesting that amine metabolites formed by nitroreduction are involved in the inhibition of mouse CYP2B enzymes.

Administration, Oral↗