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PubMed1984

Nerve growth factor-mediated enzyme induction in primary cultures of bovine adrenal chromaffin cells: specificity and level of regulation.

Primary cultures of bovine adrenal chromaffin cells provide large quantities of a homogeneous population of target cells for nerve growth factor (NGF) and, thus, are a suitable system for studying the molecular mechanism of action of NGF. In this study, we have shown that NGF mediates the specific induction of the key enzymes in catecholamine biosynthesis, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). Acetylcholinesterase (AChE), an enzyme which catalyzes the breakdown of acetylcholine, is also induced by NGF. We have compared NGF-mediated TH and AChE induction and have provided pharmacological evidence that TH induction involves a post-transcriptional, polyadenylation-dependent event (blockable by 9-beta-arabinofuranosyladenine but not by alpha-amanitin), whereas AChE induction requires transcription (blockable by alpha-amanitin). DBH and PNMT appear to be regulated via the same mechanism as TH. The time course of TH induction is such that NGF must be continuously present for at least the first 36 hr (during which time TH levels remain unchanged), and then the entire increase takes place during the subsequent 12 hr. In contrast, AChE induction proceeds linearly with time of NGF exposure. These data suggest that there may be multiple mechanisms by which NGF regulates enzyme induction. We have also compared the effects of cAMP with those of NGF. As compared to NGF, cAMP produces a different pattern of enzyme induction (in addition to TH, DBH, PNMT, and AChE, dopa decarboxylase (DDC) is also induced), it acts rapidly (a 12-hr exposure produces the full effect), and it acts only at the transcriptional level (its effects are blocked by alpha-amanitin). These data provide evidence that cAMP does not act as a second messenger for NGF with regard to enzyme induction.

Acetylcholinesterase↗
PubMed2005

Hepatocytes cultured in alginate microspheres: an optimized technique to study enzyme induction.

An important application of hepatocyte cultures is identification of drugs acting as inducers of biotransformation enzymes that alter metabolic clearance of other therapeutic agents. In the present study we optimized an in vitro system with hepatocytes cultured in alginate microspheres that allow studies of enzyme induction with excellent sensitivity. Induction factors obtained with standard inducers, such as 3-methylcholanthrene or phenobarbital, were higher compared to those with conventional hepatocyte co-cultures on collagen coated dishes. This is illustrated by activities of 7-ethoxyresorufin-O-deethylase (EROD) after incubation with 5 microM 3-methylcholanthrene (3-MC), a standard inducer for cytochrome P4501A1 and 1A2. Mean activities for solvent controls and 3-MC exposed cells were 2.99 and 449 pmol/min/mg protein (induction factor: 150) for hepatocytes cultured in microspheres compared to 2.72 and 80.6 pmol/min/mg (induction factor: 29.6) for hepatocytes on collagen coated dishes. To compare these in vitro data to the in vivo situation male Sprague Dawley rats, the same strain that was used also for the in vitro studies, were exposed to 3-MC in vivo using a protocol that guarantees maximal induction. Activities were 29.2 and 1656 pmol/min/mg in liver homogenate of solvent and 3-MC treated animals (induction factor: 56.7). Thus, the absolute activities of 3-MC exposed hepatocytes in microspheres are lower compared to the in vivo situation. However, the induction factor in vitro was even higher compared to the in vivo situation (150-fold versus 56.7-fold). A similar scenario was observed using phenobarbital (0.75 mM) for induction of CYP2B and 3A isoenzymes: induction factors for testosterone hydroxylation in position 16beta were 127.5- and 50.4-fold for hepatocytes in microspheres and conventionally cultured hepatocytes, respectively. The new in vitro system with hepatocytes embedded in solid alginate microspheres offers several technical advantages: (i) the solid alginate microspheres can be liquefied within 60s, allowing a fast and complete harvest of hepatocytes; (ii) alginate capsules are stable allowing transport and mechanical stress; (iii) high numbers of hepatocytes can be encapsulated in short periods; (iv) defined cell numbers between 600 hepatocytes, the approximate number of cells in one capsule, and 18 x 10(6) hepatocytes, the number of hepatocytes in 6 ml alginate, can be transferred to a culture dish or flask. Thus, encapsulated hepatocytes allow a flexible organization of experiments with respect to cell number. In conclusion, we optimized a technique for encapsulation of hepatocytes in alginate microspheres that allows identification of enzyme induction with an improved sensitivity compared to existing systems.

Alginates↗
PubMed1991

The influence of Org 10172, a low molecular weight heparinoid, on antipyrine metabolism and the effect of enzyme induction on the response to Org 10172.

1. We have investigated the effect of repeated s.c. Org 10172 (a low molecular weight heparinoid; Lomoparan) treatment (1000 anti-Xa units twice daily for 5 days) on antipyrine (500 mg orally) metabolism, and the effect of enzyme induction by pentobarbitone (100 mg for 12 days) on the pharmacokinetics and pharmacodynamics of Org 10172 following an intravenous bolus injection of 3250 anti-Xa units. 2. Org 10172 treatment caused a small increase in the formation rates of all antipyrine metabolites (P less than 0.05), while the overall kinetics of antipyrine did not change significantly. 3. Oxidative enzyme induction by pentobarbitone, as demonstrated by an increased clearance of antipyrine, was associated with an increase in the area under the anti-thrombin activity vs time curve (P less than 0.05). No influence was seen on the kinetics of plasma anti-Xa and thrombin generation inhibiting (TGI) activity. 4. The pharmacodynamics of Org 10172, as determined by clotting tests, was not influenced by enzyme induction. 5. The clinical relevance of these observations is likely to be limited.

Administration, Oral↗
PubMed1983

Effect of insulin-treatment on age-dependent decrease of lipogenic enzyme induction.

The effects of insulin-treatment on induction of liver lipogenic enzymes by a fat-free diet were investigated in 1-, 2- and 9-month-old rats. The magnitudes of the induction of the enzymes were very high in 1-month-old rats and decreased with aging (Iritani, N., Fukuda, H. and Fukuda, E. (1981) Biochim. Biophys. Acta 665, 636). The induction of lipogenic enzymes was not affected by insulin injection in young rats. In 9-month-old rats, however, although the maximal magnitudes of the induction were not affected by the insulin injection, the lag periods of the induction were shortened. The lipogenic enzyme induction in 9-month-olds did not correlate with plasma insulin level but paralleled changes in the insulin binding capacities to liver plasma membranes and adipocytes. The results suggest that insulin binding is implicated in age-dependent decrease of lipogenic enzyme induction, and support our previous report (Iritani, N., Fukuda, H., Tashiro, S. and Ikeda, Y. (1982) J. Biochem. 92, 569).

Acetyl-CoA Carboxylase↗
PubMed1982

Differential effects of enzyme induction on antipyrine metabolite formation.

1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

Adult↗
PubMed1981

Oxidative phosphorylation, enzyme induction and rat liver regeneration: effect of phenobarbital.

In order to outline the relationship between oxidative phosphorylation, enzyme induction and rat liver regeneration, the effect of one single dose of phenobarbital (PB) on hepatic mitochondria, microsomes and DNA synthesis was investigated. Experiments were performed on intact and partially hepatectomized rats. Results and conclusions can be summarized as follows: (1) While PB has no consistent effect on mitochondrial respiration either in normal or in partially hepatectomized rats, it clearly enhances at the rate of DNA synthesis in hepatectomized rats at 24 h. This suggests that the effect of PB on DNA synthesis is independent from the mitochondrial ATP generating activity. (2) PB causes the accumulation of cytochrome P-450 in intact rat hepatocytes, but this effect is suppressed by partial hepatectomy during the first 24 h. This and the above observation on mitochondria suggest that enzyme induction in these experimental conditions is not associated with an increase in mitochondrial oxidative phosphorylation. (3) The mechanism of the influence of PB on DNA synthesis is unclear, but present data suggest that in one single dose PB may behave in two different ways: in intact liver it causes the accumulation of cytochrome P-450 and in partially resected liver it enhances the rate of DNA synthesis; mitochondria playing apparently no important role in this interaction.

Animals↗
PubMed1994

Molecular responses as indicators of marine pollution: DNA damage and enzyme induction in Limanda limanda and Asterias rubens.

During a survey from 26 August through 13 September 1991, specimens of the flatfish, Limanda limanda (dab), and the asteroid echinoderm Asterias rubens (seastar), were collected at sampling locations along transects radiating into the North Sea from the coastal zone of The Netherlands. In homogenates of liver tissue from male dab and the digestive gland (pyloric caeca) of female seastar, DNA damage (strand breaks) and induction of the cytochrome P450-dependent monooxygenase system (MO) were determined. Areas could be described with significantly increased percentages of strand breaks (lower integrity) both in dab and seastar. However, enhanced DNA strand breaks did not correspond with contamination gradients, expressed as concentrations of polychlorinated biphenyls (PCBs) or polyaromatic hydrocarbons. MO enzyme induction in the hepatic 13,000g fraction of male dab, measured as 7-ethoxyresorufin-O-deethylase activity, was significantly enhanced in response to low ambient temperatures. Some evidence was found for the facilitation of benzo[a]pyrene hydroxylase activity expressing the enzyme induction in the microsomal fraction of pyloric caeca of seastars, at increasing PCB concentrations. DNA integrity and enzyme induction elucidate the physiologic status and might be indicative for ambient impairment within restricted areas, and not necessarily related to the presence of anthropogenic or xenobiotic substances.

Animals↗
PubMedDate not supplied

Implications and consequences of enzyme induction on preclinical and clinical drug development.

1. Enzyme induction has traditionally been studied during drug development to assess the potential of drug entities to interact with concomitant medications and alter their pharmacological effects, and clearly it is an unwanted phenomenon. However, another hurdle caused by induction occurs during preclinical development via the attainment of safety data, obtained by dosing high quantities of compound to species used in toxicology assessment. This review considers the techniques that can now be utilized in drug discovery, their relevance, the pharmacokinetic aspects of this phenomenon, and it discusses the consequences and implications of induction during preclinical and clinical development. 2. It is becoming increasingly routine to employ hepatocyte cultures and novel techniques such as quantitative real-time reverse transcriptase PCR to identify enzyme inducers in vitro. The major challenge is to utilize these in vitro data to predict the consequences of induction in vivo. From an understanding of pharmacokinetic principles and low clinical doses relative to preclinical studies, there is limited potential for induction by a development candidate to significantly alter the pharmacological efficacy of a co-administered drug. 3. The most comprehensive approach when considering induction involves integrating quantitative in vitro data, information on the pharmacokinetic behaviour of the compound and the PK/PD) relationship in order to predict its consequences. The generation of this holistic strategy would enable more detailed and informed decision-making about both the suitability of molecules for development and the development strategy itself.

Animals↗
PubMed2000

Enzyme induction in the elderly: effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone.

OBJECTIVE: A clinical study on enzyme induction in elderly subjects was performed by investigation of the effect of rifampin (INN, rifampicin) on propafenone disposition. Propafenone was chosen as a model drug because of its complex metabolism that permits the simultaneous in vivo assessment of induction of phase 1 and phase 2 pathways. METHODS: Six extensive metabolizers of CYP2D6 (age, 70.5 +/- 3.5 years) ingested 600 mg rifampin once daily for 9 consecutive days. One day before the first rifampin dose and on the day of the last rifampin dose, each elderly individual received a single intravenous infusion of 70 mg unlabeled propafenone and received a single oral dose of 300 mg deuterated propafenone 2 hours later. Pharmacokinetics and pharmacodynamics of propafenone were compared before and during induction. RESULTS: Maximum QRS prolongation after oral propafenone was decreased significantly by rifampin (18% +/- 5% versus 6% +/- 3%; P < .01). There were no substantial differences in pharmacokinetics and pharmacodynamics of intravenous propafenone during induction. However, bioavailability of propafenone dropped from 30% +/- 24% to 4% +/- 3% (P < .05). After oral propafenone was administered, clearances through N-dealkylation (6 +/- 3 mL/min versus 26 +/- 16 mL/min; P < .05) and glucuronidation (178 +/- 75 mL/min versus 739 +/- 533 mL/min; P < .05), but not 5-hydroxylation, were increased by rifampin, indicating substantial enzyme induction. CONCLUSIONS: Both phase 1 and phase 2 pathways of propafenone metabolism were induced by rifampin in elderly subjects, resulting in a clinically relevant drug interaction.

Administration, Oral↗
PubMed1984

Synergistic enzyme induction by glucocorticoids and cyclic AMP observed in glioma x hepatoma cell hybrids but not in their parents.

Enzyme induction by hydrocortisone (HC) and dibutyryl cyclic AMP (dbcAMP) was studied in C6 rat glioma cells, FU5AH rat hepatoma cells, and five C6 x FU5AH hybrids. Hormone responsive enzymes from both parental lines were studied, including: tyrosine aminotransferase (TAT), alanine aminotransferase (AAT), glycerol phosphate dehydrogenase (GPDH), lactate dehydrogenase (LDH), and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP). There was no overall dominance of one parental phenotype over the other in expression of uninduced or induced enzyme activity after fusion, and the hybrids possessed some enzymatic properties characteristic of both parents. GPDH was induced by dbcAMP in all five hybrids, and TAT was induced by dbcAMP in four of the hybrids, although neither of these enzymes were induced by dbcAMP in the parents. Furthermore, synergistic induction of these enzymes by HC and dbcAMP was observed in the hybrids but not in the parents. These hybrids provide a model system to study hormone interaction in enzyme induction.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1987

Role of ornithine decarboxylase on glycolytic enzyme induction during thymocyte proliferation.

Resting rat thymocytes were stimulated to cell cycle entry and proliferation by the addition of concanavalin A and interleukin 2 to the culture medium. Maximal rats of DNA and RNA synthesis and of glycolysis with a 20-fold increase in glucose uptake were observed 48 h after stimulation. Glycolytic enzyme levels increased 3-8-fold, also reaching their maxima 48 h after mitogenic stimulation. Actinomycin D (1.3-1.5 ng/ml) completely inhibited DNA and RNA synthesis in 24- and 48-h cultured cells but showed no inhibitory effect on glycolytic enzyme induction or on enhanced glycolysis. These results suggest the presence of sufficient mRNAs for the synthesis of glycolytic enzymes even though transcription is abolished by actinomycin D. Ornithine decarboxylase activity increased rapidly up to 41-fold within 6 h after stimulation with concanavalin A and interleukin 2. This rapid increase could not be prevented by actinomycin D; however, ornithine decarboxylase activity of thymocytes was affected after 24- and 48-h culture periods. Inhibition of ornithine decarboxylase by 5 mM difluoromethylornithine completely abolished glycolytic enzyme induction. This inhibitory effect could be reversed by exogeneous putrescine. The results obtained indicate the importance of early ornithine decarboxylase activation and polyamine biosynthesis for the induction of glycolytic enzymes in proliferating thymocytes.

Animals↗
PubMedDate not supplied

Enzyme induction and comparative oxidative desulfuration of isothiocyanates to isocyanates.

Enzyme induction of oxidative metabolism of isothiocyanates to isocyanates by rat liver microsomes and comparative metabolic conversion of some isothiocyanates were investigated. Metabolic activity was assayed by trapping the isocyanate metabolites from isothiocyanates with the inclusion of 2-aminofluorene to form the respective mixed ureas as previously described for the 2-naphthyl isothiocyanate. Male F344 rats were fed either a conventional grain diet for induction with Aroclor 1254 or AIN 76A diet without antioxidant beginning 2 weeks before treatment with Aroclor 1254, beta-naphthoflavone, isosafrole, or phenobarbital. Enzymes responsible for the metabolism of 1- and 2-naphthyl isothiocyanate were inducible by all four agents, Aroclor being the best under the current induction protocol and metabolic conversion assay procedure. On the other hand, enzymes responsible for the metabolism of benzyl isothiocyanate were induced only by Aroclor and, to a lesser extent, by phenobarbital. For the comparative metabolic conversion studies, using the microsomes from Aroclor-treated rats fed a conventional grain diet, the rates of metabolic conversion followed the order of 1-naphthyl > > phenyl > benzyl and phenethyl > > propyl, ethyl, and methyl isothiocyanates.

Animals↗
PubMed1988

Lipogenic enzyme induction and incorporation of exogenous fatty acid into liver and liver nuclei.

The incorporation of exogenous fatty acid into lipids of liver and liver nuclei of rats fed diets with or without fat was compared. When [3H]palmitic acid was injected into rats, more radioactivity was incorporated into triacylglycerols and phospholipids of liver and liver nuclei from rats fed the fat-free diet than from those fed the fat diet. The results were supported further by an autoradiographic study. On the other hand, the enzyme induction and quantity of malic enzyme mRNA were decreased by fat feeding. Other lipogenic enzymes were also coordinately decreased. Thus, it may be possible that exogenous fatty acid is involved in nuclear regulation in addition to cytosolic regulation of lipogenic enzyme induction.

Animals↗
PubMed1977

Effect of enzyme induction on nephrotoxicity of halothane-related compounds.

Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent.

Anesthetics↗
PubMed1990

Increased 6-hydroxycortisol excretion in pregnant women: implication of drug-metabolizing enzyme induction.

The effect of pregnancy on hepatic drug-metabolizing enzyme activity was investigated in nine healthy pregnant women using the ratio of 6-hydroxycortisol (6-OHF), to total 17-hydroxycorticosteroid (17-OHCS) in 24-hour urine as an index of the hepatic monooxygenase activity. The values of 6-OHF and the ratio (713 +/- 250 micrograms/d and 0.323 +/- 0.242; mean +/- SD) before delivery were significantly higher than they were during early puerperium (395 +/- 145 micrograms/d and 0.114 +/- 0.055) and approximately three months after delivery (237 +/- 67 micrograms/d and 0.066 +/- 0.034). Although the values three months after delivery were comparable to those found in the nonpregnant group (n = 10; 228 +/- 48 micrograms/d and 0.081 +/- 0.031), 6-OHF values one week after delivery were significantly higher than those observed in the control group. These observations suggest that drug-metabolizing enzyme induction may occur during pregnancy.

17-Hydroxycorticosteroids↗
PubMedDate not supplied

The relationship among microsomal enzyme induction, liver weight and histological change in rat toxicology studies.

The purpose of this study was to determine what histological changes, if any, accompany liver enlargement and microsomal enzyme induction in rats administered high doses of therapeutic agents in preclinical toxicology studies. This was accomplished by evaluating a database derived from a series of 11 induction studies in rats with 10 novel compounds comprising five therapeutic classes. Results from serum enzyme chemistry analyses, gross organ weight changes, and histological analyses of the liver sections were evaluated and compared with the magnitude and extent of hepatic cytochrome P450 induction. All compounds were administrated via oral intubation once a day for the duration of the study using multiple doses, each proportionally based on body weight. During the course of these studies, serum clinical chemistry data and clinical observations were recorded. After necropsy, histopathology observations were made, and hepatic microsomes were assayed for cytochrome P450 content and associated drug-metabolizing enzymes. In some cases, cyanide-insensitive beta-oxidation of palmitoyl CoA was also assayed. Liver weight increases of 20% or greater were associated with histological evidence of hypertrophy, but neither the severity of hypertrophy nor the magnitude of liver weight increase correlated with the magnitude of drug-metabolizing enzyme elevations. Hypertrophy alone was not associated with serum enzyme increases. While there was a correlation between the incidence of increased liver weights and microsomal enzyme induction, the magnitudes of these increases were not related. Decreased serum triglycerides were often associated with elevated beta-oxidation attributed to hepatic peroxisome proliferation. It was concluded that, while slight ALT elevations occasionally were observed, hepatic microsomal enzyme induction was generally not accompanied by substantial morphological changes or elevated serum enzyme levels considered indicative of liver injury.

Administration, Oral↗
PubMed1978

Liver enzyme induction by 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (DDT) is accompanied by an increase in the specific activity of elongation factor 1.

Homogenates of liver were obtained from control rats and from rats that had received DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane]. The postmicrosomal supernatant fractions were used for the purification of elongation factor 1 by hydroxyapatite chromatography and phosphocellulose chromarography. The amount of binding factor present was essentially the same for both groups of animals, but the specific activity, as measured by the binding assay, was about twice as high in the DDT-treated preparations. After sucrose-gradient sedimentation, the difference in specific activity was found to reside in the low-molecular-weight (50000) form of elongation factor 1. The implications of an increased reactivity of elongation factor 1 during the induction of membrane enzymes are discussed.

Animals↗