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PubMed1975

Enzyme induction.

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Carnitine Acyltransferases↗
PubMed2005

A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction.

In vitro models of the liver using isolated primary hepatocytes have been used as screens for measuring the metabolism, toxicity and efficacy of xenobiotics, for studying hepatocyte proliferation, and as bioartificial liver support systems. Yet, primary isolated hepatocytes rapidly lose liver specific functions when maintained under standard in vitro cell culture conditions. Many modifications to conventional culture methods have been developed to foster retention of hepatocyte function. Still, not all of the important functions -- especially the biotransformation functions of the liver -- can as yet be replicated at desired levels, prompting continued development of new culture systems. In the first part of this article, we review primary hepatocyte in vitro systems used in metabolism and enzyme induction studies. We then describe a scalable microreactor system that fosters development of 3D-perfused micro-tissue units and show that primary rat cells cultured in this system are substantially closer to native liver compared to cells cultured by other in vitro methods, as assessed by a broad spectrum of gene expression, protein expression and biochemical activity metrics. These results provide a foundation for extension of this culture model to other applications in drug discovery -- as a model to study drug-drug interactions, as a model for the assessment of acute and chronic liver toxicity arising from exposure to drugs or environmental agents; and as a disease model for the study of viral hepatitis infection and cancer metastasis.

Animals↗
PubMed1986

The synergistic interaction of hydrocortisone and dibutyryl cyclic AMP during enzyme induction in hybrids between rat C6 glioma cells and FU5AH hepatoma cells.

The hormone-responsive enzymes tyrosine aminotransferase and glycerol-3-phosphate dehydrogenase were studied with respect to current models of the mechanism of glucocorticoid/cAMP interaction during the induction of enzyme activity in responsive cell hybrids between rat C6 glioma cells and rat FU5AH hepatoma cells. The results of experiments involving protein and mRNA synthesis inhibitors, sequential addition of inducers, and the assay of cyclic-AMP-dependent protein kinase could not be adequately explained by any one model of inducer interaction. Comparison of the hybrid clones revealed the presence of factors that may modify induction but that are not essential for synergistic induction.

Amanitins↗
PubMed1996

Effects of doxylamine succinate on thyroid hormone balance and enzyme induction in mice.

The effects of doxylamine (as the succinate salt) on microsomal enzyme activity and serum thyroid hormone levels were examined in B6C3F1 mice following dietary exposure for 7 or 15 days (0, 40, 375, 750, or 1500 ppm in diet, expressed as free base doxylamine). In addition, the hepatic P450 enzyme inducer sodium phenobarbital (375 ppm, expressed as free acid phenobarbital) was used as a positive control for CYP2B induction. Exposure of mice to doxylamine produced dose-related increases in liver weight at both time points. Liver weights were also increased in the phenobarbital-treated mice. Doxylamine treatment caused a dose-dependent increase (up to 2.6-fold) in liver microsomal cytochrome P450 in both male and female mice, at both time points. Analyses of the activities of various hepatic microsomal cytochromes P450 indicated that doxylamine caused a marked induction of CYP2B enzymes. This was demonstrated by a large increase in the O-dealkylation of 7-pentoxyresorufin (up to 38-fold) and the 16beta-hydroxylation of testosterone (up to 6.9-fold), both of which are indicative of CYP2B induction. In addition, like phenobarbital, doxylamine treatment resulted in a modest induction of CYP3A and CYP2A enzymes and approximately a 50% increase in thyroxine-glucuronosyltransferase activity. Doxylamine did not appear to induce P450 enzymes in the CYP1A, CYP2E, or CYP4A enzyme subfamilies. None of the enzyme-inducing effects of doxylamine could be distinguished from those of phenobarbital. These results suggest that doxylamine is a phenobarbital-type inducer of liver microsomal cytochrome P450 in B6C3F1 mice. Exposure to either doxylamine or phenobarbital also resulted in decreases in serum thyroxine (T4) levels (approximately 80% of control) with compensatory increases in serum thyroid-stimulating hormone levels (approximately 4-fold). No clear changes in serum triiodothyronine levels were apparent. These findings are consistent with the hypothesis that doxylamine increases the activity of those hepatic enzymes involved in T4 metabolism.

Animals↗
PubMed1991

Drug metabolizing enzyme induction by simple diaryl pyridines; 2-substituted isomers selectively increase only conjugation enzyme activities, 4-substituted isomers also induce cytochrome P450.

Pyridine derivatives bearing aryl containing substitutions at the 2- and 4-position were administered to male rats, daily, for 3 days at 75 mg/kg. All five 2-substituted pyridines investigated increased rat hepatic UDP-glucuronosyltransferase activities toward three aglycones (morphine, p-nitrophenol, and 1-naphthol) without inducing cytochrome P450. Two of the 4-substituted pyridines investigated (4,4'-dipyridyl, 4-benzylpyridine) significantly induced cytochrome P450. UDP-glucuronosyl-transferase activity by the 4-substituted pyridines was increased to a much lesser extent than seen for the equivalent 2-isomers. The two 4-substituted pyridines eliciting induction of cytochrome P450 were also the only 4-isomers which increased cytosolic glutathione-S-transferase activity, but three 2-substituted pyridines (2-benzoylpyridine, 2-benzylpyridine, and trans-1,2-bis(2-pyridyl)ethylene) increased this activity in the absence of cytochrome P450 induction. No compound investigated induced cytosolic sulfotransferase activity. Diaryl compounds lacking a heterocyclic ring did not increase any of the investigated drug metabolizing enzyme activities. For simple diarylpyridines, the position of substitution on the pyridine ring rather than the nature of the substituent appears to be a major determinant for selective induction of UDP-glucuronosyltransferases without concurrent increases in cytochrome P450. The 2-substituted pyridines were consistently selective inducers of only Phase II or conjugation enzymes. The 4-substituted pyridines included derivatives that could selectively induce Phase II and nonselectively induce both Phase I and Phase II and one derivative that induced neither.

Animals↗
PubMed1986

Turing structures in an enzyme-induction system with gap junction-mediated non-linear diffusion.

Two cells, each containing a reaction system modeling genetic induction, are coupled by diffusion. The substrate is moving through gap junctions, the number of which is regulated by the adjacent cells. This leads to a non-linear substrate diffusion term in the rate equations. Stability analysis reveals the conditions for the emergence of stable asymmetric solutions (dissipative structures). Due to non-linear diffusion rigid restrictions on the ratio of the two diffusion constants no longer exist. We demonstrate that substances operating as regulators of intercellular communication and participating in cellular metabolism may exhibit morphogenetic functions.

Animals↗
PubMed1983

Enzyme induction with high doses of rifampicin in Wistar rats.

Hepatic microsomal enzyme activities were determined in female Wistar rats after 1 and 8 days of oral administration of high doses of rifampicin (RFP) (400 mg/kg/day). After 8 days, the level of cytochrome P-450 doubled and the activities of NADPH-cytochrome c reductase and benzphetamine N-demethylase were significantly increased. The observed changes in enzymic activities are consistent with the possibility that RFP induces a special form of cytochrome P-450, responsible for the metabolism of the antibiotic (demethylation and reduction of rifampicin quinone). Considering the role of the endoplasmic reticulum in lipid metabolism, the inducing activity of RFP might also contribute to the observed accumulation of lipids in the liver.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1995

Human placental cytochrome P450 and quinone reductase enzyme induction in relation to maternal smoking.

Components of cigarette smoke such as cadmium and polycyclic aromatic hydrocarbons have been shown to induce quinone reductase (QR) activity in placental explants. This study examines the relationship of maternal smoking habit and maternal plasma cotinine concentration with the activities in vitro of both QR and the cytochrome P450 (CYP1A) marker ethoxyresorufin O-deethylase (EROD) in placental tissue. Maternal plasma samples were taken at Week 34 of gestation, and placental tissues were obtained at term. Plasma cotinine concentrations were determined by high-performance liquid chromatography. Trophoblast cytosolic QR and microsomal EROD activities were measured by resazurin reduction and ethoxyresorufin O-dealkylation respectively. QR activity was inhibited 70% by a mixture of dicoumarol (1 microM) and rutin (20 microM). Plasma cotinine concentrations correlated significantly (P < 0.001) with both declared smoking rate (r = 0.67, N = 37) and placental EROD activity (r = 0.63, N = 36), but not with QR activity, whether measured as total QR activity or specifically as either DT-diaphorase or carbonyl reductase. It is concluded that smoking up to 40 cigarettes per day induces EROD but does not affect QR activity in the placenta at term.

Cotinine↗
PubMed1987

Effect of enzyme induction and inhibition on the fate of metronidazole and tinidazole in the rat.

The excretion routes of intact metronidazole and tinidazole were studied in rats kept in metabolism cages and cannulated for continuous bile collection. The nitroimidazoles were given intraarterially either alone or after a 5-day pretreatment with phenobarbitone (70 mg/kg/day intravenously) or after a single dose of cimetidine (50 mg/kg intraarterially). After 30 mg/kg, 27.0% of the metronidazole dose was excreted intact in 24-hr urine and 2.2% in bile. After tinidazole, the recoveries of the intact drug in urine and bile were 48.1% and 1.7%, respectively. After 90 mg/kg, the total recoveries of both drugs were 25-28% smaller than after 30 mg/kg. Phenobarbitone pretreatment did not affect metronidazole levels in plasma but decreased tinidazole levels at 4 hrs. The 24-hr recoveries of the intact nitroimidazoles in urine were significantly reduced by phenobarbitone while the 24-hr bile recoveries were not. Cimetidine treatment enhanced both metronidazole (at 1, 2 and 3 hrs) and tinidazole (only at 1 hr) concentrations in plasma, but this shift was not reflected in the 24-hr urine recoveries of the intact nitroimidazoles. Cimetidine doubled, however, the 24-hr bile recovery of the intact tinidazole. The calculations of the apparent degree of metabolism, assuming no methodological losses, showed that phenobarbitone increased the metabolism of tinidazole by about 62% and that of metronidazole only by about 16%. The effect of a single dose of cimetidine was negligible.

Animals↗
PubMedDate not supplied

The effect of enzyme induction and inhibition on the disposition of the xanthine-related nootropic drug ethimizol in perfused liver and hepatocytes of rats.

The once-through perfused (18 ml/min) rat liver preparations from vehicle-, phenobarbital (PB)-, and 3-methylcholanthrene (3-MC)-treated rats were used for the study of 14C-ethimizol [4,5-di(methylcarbamoyl)-1-ethyl-imidazole] elimination after input concentrations of 5, 25, 50, and 100 microM. The steady state hepatic extraction ratios decreased with increasing ethimizol inputs and were (mean +/- SD): for vehicle-treated rats, 0.361 +/- 0.038, 0.193 +/- 0.018, 0.141 +/- 0.010, and 0.100 +/- 0.011; for PB-treated rats, 0.578 +/- 0.093, 0.393 +/- 0.039, 0.302 +/- 0.028, and 0.236 +/- 0.032; and for 3-MC-treated rats, 0.913 +/- 0.057, 0.783 +/- 0.130, 0.619 +/- 0.097, and 0.447 +/- 0.053, for the respective concentrations. In recirculating experiments both PB and 3-MC increased ethimizol elimination, but the effect of the latter was considerably greater. 3-MC was also more effective than PB in enhancing the rate of formation and subsequent biotransformation of the primarily formed ethimizol metabolites, 4-carbamoyl-1-ethyl-5-methylcarbamoyl-imidazole and 4,5-di(methylcarbamoyl)-imidazole. Elimination of ethimizol was inhibited in suspension of rat hepatocytes by SKF 525-A at concentrations of 10 and 100 microM by 63% and 60%, respectively, and by alpha-naphthoflavone, at the same concentrations, by 71% and 85%, respectively. Their simultaneous addition almost completely inhibited ethimizol biotransformation. An increase of the ethimizol elimination rate in single-pass rat liver perfusion by 55% was observed in preparations from rats treated by ethimizol in their drinking water, whereas the liver/body weight ratio, microsomal protein, and cytochrome P-450 content remained unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Radioprotective effects of 2-(allylthio)pyrazine an experimental chemopreventive agent: effects on detoxifying enzyme induction.

2-(Allylthio)pyrazine (2-AP), which is effective in suppressing constitutive and inducible cytochrome P450 2E1 expression, exhibits hepatoprotective and chemopreventive effects. The radioprotective effects of 2-AP were examined in animals in association with the expression of microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs). 2-AP pretreatment (100 mg/kg/day, for 2 days) prior to total body irradiation (TBI) at the dose of 8 Gy increased the 30 day survival rate of mice to 91% from 48% in TBI alone. 2-AP caused an increase in the mean survival time of mice exposed to 9 Gy of TBI. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray radiation resulted in hepatocyte degeneration in the surviving animals at day 1 through day 22 with certain extents of necrosis observed at early times, whereas 2-AP pretreatment protected the liver against ionizing radiation with no hepatic necrosis being observed. Mice irradiated at the dose of 8 Gy showed time-related decreases in the counts of WBC, RBC and platelet. 2-AP treatment, however, failed to protect the peripheral blood cells against gamma-irradiation and resulted in no improvement in the ratio of myeloid to erythroid bone marrow cells, as compared to TBI alone. Northern blot analysis revealed that exposure of mice to 8 Gy of TBI plus 2-AP exhibited greater mEH and mGSTA3 mRNA levels in the liver than those with TBI alone, although mGSTP1 mRNA level failed to be altered. Studies were also extended to determine the effects of 0.5 Gy gamma-irradiation in combination with 2-AP on the expression of hepatic mEH and GST genes in rats. Whereas mEH, rGSTA2, rGSTA3 and rGSTA5 mRNA levels were elevated 2- to 2.8-fold at 24 h after 2-AP treatment at the dose of 30 mg/kg, rats exposed to both 2-AP and 0.5 Gy of irradiation showed greater relative increases in the mRNAs. 2-AP enhanced the mEH and rGSTA2 gene expression to greater extents at day 1 after irradiation than after 3-5 consecutive daily treatment. The radiation-inducible mRNA levels of rGSTA3/5 and rGSTM1/2 were affected less by 2-AP pretreatment than were those of mEH and rGSTA2. These results demonstrate that 2-AP exhibits radioprotective efficacy against gamma-ray ionizing radiation in both mice and rats, which might be associated with enhanced expression of mEH and GST genes, but not with hematological improvement.

Animals↗