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PubMed1989

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↗
PubMed1993

Induction of rat liver drug-metabolizing enzymes by heterocycle-containing mono-, di-, tri- and tetra-arylmethanes.

The effect of a nitrogen heterocycle constituent on the ability of arylmethanes to induce phase I and phase II drug-metabolizing enzymes has been examined. Rats were treated with tetra-, tri-, di- or monoarylmethane compounds daily for 3 days at a dose of 75 mg/kg. Induction of UDP-glucuronosyltransferase (morphine) activity was seen with twelve of the eighteen compounds investigated, and for three compounds it occurred independent of any induction of cytochrome P450. Induction of glutathione S-transferase activity was seen with ten of the compounds and was generally paralleled by changes in overall cytochrome P450 concentration and in both pentoxyresorufin and erythromycin dealkylase activities. Major induction of ethoxyresorufin deethylase activity was only apparent with two diarylmethanes that contained a 1-substituted imidazole moiety. UDP-glucuronosyltransferase (1-naphthol) activity was coinduced by these two compounds. A third compound, diphenyl-4-pyridylmethane, induced UDP-glucuronosyltransferase (1-naphthol) activity without increasing ethoxyresorufin deethylase activity. Cytosolic sulfotransferase activity was not induced by the administration of any compound in this study. Among arylmethane derivatives, the presence of two aryl groups appeared to be a minimum requirement for induction of drug-metabolizing enzymes. If one of the aryl groups was not a heterocycle, or if the nitrogen atom of the heterocycle was sterically hindered, major induction of cytochrome P450 did not occur. With triarylmethanes, induction was independent of whether the heterocycle was imidazole, pyridine or pyrimidine.

Animals↗
PubMed1994

Effects of testosterone, hypophysectomy and growth hormone treatment on clofibrate induction of peroxisomal beta-oxidation in female rat liver.

Induction of peroxisomal beta-oxidation by clofibrate under altered hormonal states was investigated in female rat liver. Treatment of rats with clofibric acid (CPIB) caused a significant increase in hepatic peroxisomal beta-oxidation, with female rats being less responsive than males (4.2- vs 12.2-fold increase). However, testosterone treatment following ovariectomy of female rats resulted in an enhanced response to CPIB, giving an induction (11.7-fold) comparable to that seen in male rats. Hypophysectomy of female rats also enhanced the induction (8.2-fold compared with 5.1-fold), suggesting a suppressive effect of a pituitary-dependent factor on CPIB induction of peroxisomal beta-oxidation. Continuous infusion of growth hormone to the hypophysectomized female rats suppressed the enhanced induction nearly to the initial level (6.1-fold). The stimulatory effects of testosterone and hypophysectomy on the enzyme induction were additive. These findings suggest the involvement of growth hormone, as well as male sex hormone, in regulating the responsiveness to CPIB induction of peroxisomal beta-oxidation in rat liver.

Animals↗
PubMed1990

Induction of hepatic cytochrome P-450 mediated alkoxyresorufin O-dealkylase activities in different species by prototype P-450 inducers.

The induction of cytochrome P-450-mediated alkoxyresorufin O-dealkylase activities by various xenobiotics was examined in liver from a variety of animal species in order to gain insights into the substrate specificities of the induced P-450s. We found that forms of cytochrome P-450 capable of mediating the O-dealkylation of the short-chain phenoxazone ethers methoxy-, ethoxy- and propoxyresorufin were highly induced by 3-methylcholanthrene-type inducers and by Aroclor-1254 in all species tested, although there were species differences in the relative turnover rates for the various substrates. For example, in hamster liver the turnover rates for the short-chain resorufin ethers decreased in the following order: methoxy greater than ethoxy much greater than propoxy, while in the rat liver almost the exact opposite order was observed: ethoxy = propoxy much greater than methoxy. In contrast, the degree of induction by phenobarbital-type inducers of isozymes catalyzing the O-dealkylation of pentoxy- or benzyloxyresorufin was highly species-dependent. Thus, F344/NCr rats, B6C3F1 mice and NZB rabbits showed the greatest (greater than 20-fold) induction of these activities, either by phenobarbital or Aroclor-1254, while Mongolian gerbils showed intermediate levels of induction and Syrian golden hamsters exhibited very low induction. In the Japanese quail, phenobarbital- or DDT-treatment resulted in minimal induction of pentoxy- or benzyloxyresorufin O-dealkylase activity, although significant induction of the latter activity occurred following treatment with 5,6-benzoflavone or with Aroclor-1254. Since substrate specificities of most enzymes can be rationalized based upon differences in the steric requirements at the enzyme active site, we employed molecular modeling techniques to calculate the molecular dimensions of the alkoxyresorufins. Surprisingly, the minimal energy conformations in vacuo of each of the resorufin ethers examined are essentially planar. However, alternative configurations, especially for the pentoxy- and benxyloxy-ethers, having greater three-dimensional bulk are also energetically possible.

Animals↗
PubMed1984

Inhalation pharmacokinetics: evaluating systemic extraction, total in vivo metabolism, and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios.

A method is described for evaluating systemic extraction of soluble vapors during inhalation exposures. The physiological basis of the method is the inability to achieve complete equilibrium of vapor between arterial blood and inhaled air whenever there is substantial extraction of the soluble vapor during a single pass through the systemic circulation. The technique was applied to estimate styrene extraction ratios at the end of 6-hr exposures in male rats exposed to various concentrations of inhaled styrene. From extraction ratios and several physiological constants, metabolic constants were evaluated for styrene metabolism in vivo. In naive rats, the maximum velocity of metabolism was 10.0 mg/kg/hr, and Km was of the order of 0.2 mg/liter. Pretreatment with pyrazole (320 mg/kg, 1/2 hr before exposure) essentially abolished in vivo styrene metabolism, while pretreatment with phenobarbital (80 mg/kg/day for the 4 days before styrene exposure) increased Vmax about sixfold. Prior exposure to styrene (1000 ppm for 6 hr/day on each of 4 days before experimentation) increased Vmax by a factor of 2. Significant induction of styrene metabolism in vivo was observed in 24-hr continuous exposure to 400, 600, or 1200 ppm. A curve fitting routine was employed with a physiological model of styrene inhalation kinetics to estimate the dynamics of the induction process in the 24-hr exposures. At 400 ppm, induction began after a lag of 15.5 hr, had a half-life of 3.5 hr, and reached 2.7 times the Vmax in naive rats. At 600 ppm, it began after 10.6 hr, proceeded with a half-life of 2.2 hr, and increased Vmax by 3.4 times. At 1200 ppm, induction began earlier, 4.6 hr, and reached a greater value, 4.4 times Vmax, but had a half-life similar to that at 600 ppm. No induction occurred in 48-hr exposure to 200 ppm. Induction complicates kinetic modeling of continuous inhalation with soluble, well-metabolized vapors because it is time and concentration dependent. These methods should prove useful for studying the in vivo metabolism of other soluble, well-metabolized vapors and for examining the time course of induction of the metabolizing enzymes for these chemicals.

Air↗
PubMed1990

Characteristics of the suppressive effect of nicardipine on peroxisome induction in rat liver.

In vivo administration of nicardipine, a known calcium antagonist, suppressed the clofibrate-evoked induction of activities of peroxisomal enzymes, such as catalase, the peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase and mitochondrial carnitine palmitoyltransferase in rat liver. On a time-course study, the suppression of induction in the activities of the peroxisomal fatty acyl-CoA oxidizing system and carnitine acetyltransferase was found at 5 days after the treatment, whereas the induction by clofibrate was already observed at 1 day after the treatment, suggesting that in the process of peroxisome induction by clofibrate there might be two steps, i.e., a triggering step and an enhancing step, and nicardipine might act as suppressor for the later step. The precursor-incorporation studies with [3H]leucine showed that the rate of the synthesis of the peroxisomal bifunctional enzyme was increased by 4.2-fold after clofibrate-treatment, whereas nicardipine suppressed this enhancement to only 2.2-fold of the control. The rate of degradation of this enzyme was not affected by any treatment. These results show that nicardipine affects the regulation mechanism of the biosynthesis of this enzyme. Nicardipine showed hardly any suppressive-effect on the hepatic peroxisomal enzyme induction observed in high-fat diet fed rat. Furthermore, the suppression of clofibrate-evoked induction of peroxisomal enzymes was observed also in mice. These interesting findings suggest that there is a difference in the mechanism of peroxisome proliferation and/or the induction of peroxisomal enzymes between clofibrate and physiological conditions, such as high-fat diet feeding. The suppression of drug-induced peroxisome proliferation by calcium antagonists may help in dissecting the causal relationship between the multiple effects mediated by peroxisomal proliferators.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1995

Temperature induction of bacteriophage lambda mutants in Escherichia coli.

The paper presents temperature induction in Escherichia coli cells with phage lambda on the target-protein production and cell growth. Replicated lambda-DNA particles in the Q- and S- mutants remain naked for a longer time by preventing DNA packaging and cell lysis, and therefore the expression of the foreign genes is high. However, the parasitic infection of phage-lambda causes on significant losses of host cell viability in the induction phase. The temperature effects on cell growth and targeted-gene product formation were investigated. Gene amplification was found to be growth phase dependent for both Qam73 (Q mutation) and Sam100 (S mutation) mutants. Maximum induction occurs in the early exponential phase and under the optimal cell density. The total beta-galactosidase activity at this optimal induction condition increases roughly 8-10-fold with respect to that without thermal induction. To maximize the induction efficiency for the gene-product beta-galactosidase activity, several operating parameters were investigated. In this study, temperature induction is strongly dependent upon the population density of 'susceptible' cells at which time the temperature is shifted to 38-42 degrees C. This may be due to the 'threshold' population density to regulate the infection of lambda to hosts and control the productivity of target gene expression.

Bacteriophage lambda↗
PubMed1990

Differential effects of 12-O-tetradecanoylphorbol 13-acetate on cytochrome P-450-dependent monooxygenase activities in rat hepatoma cells: induction of P-450I and suppression of P-450II.

We have studied the effects of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) on cytochrome P-450-dependent monooxygenase activities in several differentiated and dedifferentiated Reuber rat hepatoma cell lines using aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH), ethoxyresorufin O-deethylase (EROD), and aldrin epoxidase (AE) as test systems. The following results were obtained: (1) Exposure of cultures to 400 nM TPA for 18-24 h increased AHH activities in the differentiated lines 2sFou, H41IEC3/G- and Fao as well as in the dedifferentiated line 5L, 1.5-2.5-fold. The phorbol ester did not affect AHH activity in the dedifferentiated line H5. (2) EROD, a marker for P-450I, was induced by the phorbol ester to a similar degree as AHH. (3) A monoclonal antibody directed against P-450I strongly inhibited the AHH activity induced by TPA. (4) The onset of AHH or EROD induction by TPA was much later than that elicited by benz[a]anthracene. (6) In contrast to the induction of AHH and EROD, TPA decreased AE activity, a marker for P-450II, by about 50% in all the cell lines containing this monooxygenase activity. (7) The half-maximum-effect concentration of TPA for inducing or suppressing AHH and AE, respectively, was approximately 20 nM. (8) TPA did not interfere with AHH induction by benz[a]anthracene. However, the phorbol ester moderately decreased AHH induction and markedly suppressed AE induction by dexamethasone. The results indicate that TPA simultaneously induces P-450I and suppresses P-450II forms in rat hepatoma cells. P-450I induction by TPA in these cells did not appear to depend on their status of differentiation. Furthermore, the results suggest that the mechanism of P-450I induction by TPA differs from that elicited by polycyclic aromatic hydrocarbons or glucocorticoids.

Animals↗
PubMed1985

Weak androgen reduces the rate constant of beta-glucuronidase induction.

Administration of androgen to mice induces kidney beta-glucuronidase. Measuring beta-glucuronidase activity, rate of beta-glucuronidase synthesis, beta-glucuronidase mRNA activity and beta-glucuronidase mRNA concentration, the time course of induction was compared using a strong androgen, dihydrotestosterone (DHT), and a weakly androgenic progestin, medroxyprogesterone acetate (MPA). Using MPA resulted in a longer lag, a 3-4-fold slower rate of induction as defined by the forward rate constant, ka, a lower final extent of induction, and a slightly lower turnover constant, kb. Differences in kinetics of induction were consistent for all 4 measured parameters, and mimicked previously described genetic differences in these rate constants. The coordinate induction of beta-glucuronidase protein and beta-glucuronidase mRNA indicates that the response to androgen is regulated at a pre-translational level. That substitution of MPA for DHT decreases ka, rather than increasing kb, suggests that induction of beta-glucuronidase follows an increased rate of mRNA synthesis rather than a decreased rate of mRNA turnover. Finally, the results are consistent with a model in which the kinetic constants for beta-glucuronidase induction are dependent on the concentration of receptor molecules in the active conformational state.

Animals↗
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↗
PubMed2006

Fall in diffusing capacity associated with induction therapy for lung cancer: a predictor of postoperative complication?

BACKGROUND: Pulmonary resection after induction therapy is associated with high rates of pulmonary morbidity and mortality. However, the impact of induction therapy on the pulmonary toxicity and associated pulmonary complications has not been fully investigated in the setting of lung cancer surgery. METHODS: We assessed the 66 consecutive patients who underwent a pulmonary resection after induction therapy, 48 of whom received chemoradiotherapy and 18, chemotherapy alone. Results of pulmonary function before and after induction therapy were compared, and logistic regression analyses utilized to explore the risk factors of pulmonary morbidity. RESULTS: After induction therapy, forced expiratory volume in 1 second (FEV1) was increased significantly (from 2.28 +/- 0.61 L to 2.40 +/- 0.62 L; p < 0.05); however, percent vital capacity (%VC) and FEV1/FVC did not change significantly. The diffusing capacity of lung for carbon monoxide (D(LCO)) was decreased significantly by 21% (from 90.3% +/- 18.3% to 71.1% +/- 12.5%; p < 0.0005). Patients with respiratory complication showed lower predicted postoperative %FEV1 (49.5% +/- 11.1% versus 57.2% +/- 14.2%; p = 0.031) and predicted postoperative %Dlco (41.9% +/- 8.0% versus 55.4% +/- 10.1%; p < 0.0001) results than those without complications. Univariate and multivariate analyses revealed that predicted postoperative %D(LCO) alone was an independent factor to predict postoperative pulmonary morbidity. CONCLUSIONS: For patients who undergo a pulmonary resection after induction therapy, predicted postoperative %D(LCO) is more important to predict pulmonary morbidity rather than static pulmonary function (predicted postoperative %VC or %FEV1). The decrease in D(LCO) is thought to reflect a limited gas exchange reserve, caused by the potential toxicity of chemotherapy or chemoradiotherapy. We believe that the impact of diffusion limitation after induction therapy should to be emphasized to decrease the pulmonary morbidity.

Adenocarcinoma↗
PubMed2004

Biphasic induction of heme oxygenase-1 expression in macrophages stimulated with lipopolysaccharide.

Time course relationship between inductions of iNOS and HO-1 was evaluated in RAW264.7 macrophages stimulated with LPS. Expression of HO-1 mRNA increased in a biphasic pattern, but that of xCT (cystine transporter) and iNOS mRNA increased in a monophasic manner. HO-1 protein level increased also in a biphasic manner, at 1-2 h and again between 8 and 24 h. However, iNOS protein began to increase at 4 h, quickly reaching a high level in a monophasic induction pattern. Production of NO* began to occur at 6 h and nitrite continued to accumulate in the culture medium. Total GSH level decreased markedly (50% of control) by 2 h, began to recover at 4 h, returned to control level by 6 h and increased above the control level during 10-24 h. Collectively, these results indicated that overproduced O2*- depletes GSH and triggers induction of xCT, HO-1, iNOS and HO-1 expression in sequence. Most notably, the second-phase induction of HO-1 was caused by overproduced NO*, resulting from LPS-derived iNOS induction. When this iNOS-derived delivery of NO* was combined with prior depletion of GSH using buthioninesulfoximine, an inhibitor of GSH biosynthesis, induction of HO-1 was potentiated. Furthermore, upon such super-induction of HO-1, NO* production was inhibited along with suppression of iNOS expression. Collectively, these results suggested that HO-1 is induced in a biphasic manner, sequentially by the overproduced O*2- and NO*, and the elevated HO-1 suppresses the production of these radicals in an auto-regulatory manner. This may allow the macrophages to survive from injuries that can be caused by concomitant oxidative and nitrosative stresses initiated by the LPS-driven oxidative burst.

Animals↗
PubMed2005

Induction of Cyp1a1 and Cyp1b1 and formation of DNA adducts in C57BL/6, Balb/c, and F1 mice following in utero exposure to 3-methylcholanthrene.

Fetal mice are more sensitive to chemical carcinogens than are adults. Previous studies from our laboratory demonstrated differences in the mutational spectrum induced in the Ki-ras gene from lung tumors isolated from [D2 x B6D2F1]F2 mice and Balb/c mice treated in utero with 3-methylcholanthrene (MC). We thus determined if differences in metabolism, adduct formation, or adduct repair influence strain-specific responses to transplacental MC exposure in C57BL/6 (B6), Balb/c (BC), and reciprocal F1 crosses between these two strains of mice. The induction of Cyp1a1 and Cyp1b1 in fetal lung and liver tissue was determined by quantitative fluorescent real-time PCR. MC treatment caused maximal induction of Cyp1a1 and Cyp1b1 RNA 2-8 h after injection in both organs. RNA levels for both genes then declined in both fetal organs, but a small biphasic, secondary increase in Cyp1a1 was observed specifically in the fetal lung 24-48 h after MC exposure in all four strains. Cyp1a1 induction by MC at 4 h was 2-5 times greater in fetal liver (7000- to 16,000-fold) than fetal lung (2000- to 6000-fold). Cyp1b1 induction in both fetal lung and liver was similar and much lower than that observed for Cyp1a1, with induction ratios of 8- to 18-fold in fetal lung and 10- to 20-fold in fetal liver. The overall kinetics and patterns of induction were thus very similar across the four strains of mice. The only significant strain-specific effect appeared to be the relatively poor induction of Cyp1b1 in the parental strain of B6 mice, especially in fetal lung tissue. We also measured the levels of MC adducts and their disappearance from lung tissue by the P(32) post-labeling assay on gestation days 18 and 19 and postnatal days 1, 4, 11, and 18. Few differences were seen between the different strains of mice; the parental strain of B6 mice had nominally higher levels of DNA adducts 2 (gestation day 19) and 4 (postnatal day 1) days after injection, although this was not statistically significant. These results indicate that differences in Phase I metabolism of MC and formation of MC-DNA adducts are unlikely to account for the marked differences observed in the Ki-ras mutational spectrum seen in previous studies. Further, the results suggest that other genetic factors may interact with chemical carcinogens in determining individual susceptibility to these agents during development.

Animals↗
PubMed2006

Bifunctional modulating effects of an indigo dimer (bisindigotin) to CYP1A1 induction in H4IIE cells.

In this study, we measured and characterized the bifunctional effects of a newly identified natural compound-bisindigotin (SLY-1), isolated from leaf extracts of Isatis indigotica, to CYP1A1/EROD activities in H4IIE cells. The compound, SLY-1 (1muM) elicited a transitory and significant induction of CYP1A1 RNA/protein levels and EROD activities in the cells. Maximum levels of CYP1A1 expression and EROD induction were attained at 8 and 12h of post-treatment, respectively. Thereafter the induction decreased significantly. Similar profile of CYP1A2 and CYP1B1 mRNA induction was observed. In contrast TCDD elicited CYP1A1/EROD induction was persistent. The transitory effect by SLY-1 is most likely due to the clearance of SLY-1 by cellular metabolism. Taken together the observation indicated that SLY-1 is an Ah receptor agonist for CYP1A1/CYP1A2/CYP1B1/EROD induction. Interestingly in the TCDD/SLY-1 cotreatment study, although synergistic effects on CYP1A1 expression and EROD induction were observed at 4-8h, significant inhibitory effects to TCDD induced CYP1A1 protein and EROD activity were detected at 12-24h of post-treatment. Because there was no significant reduction of CYP1A1, CYP1A2 or CYP1B1 transcript levels between TCDD- and TCDD/SLY-1 treated cells, the data pointed to the translational and/or post-translational inhibitory effect. The cellular signal transduction system may be modulated following exposure to SLY-1. To investigate the possible mechanisms involved, various specific kinase inhibitors or activators (chelerythrin, PD98059, U0126, ZM336372, SB202190, PKA inhibitor PKI (6-22) amide, and dbcAMP) were used for the assessment. Chelerythrine, PD98059 or dbcAMP treatment in TCDD induced cells showed significant inhibitory effects on CYP1A1 mRNA/protein expressions and EROD activities. U0126 had no observable EROD inhibitory effect. ZM336372 or SB202190 showed inhibition only at EROD activities. The results indicated that the SLY-1 inhibitory effect was possibly not mediated by the cAMP/PKA, PKC or MEK pathways. Nevertheless our results indicate that SLY-1 is not only an inducer of the CYP1A1 system, but also a potent inhibitor of CYP1A1 enzyme.

Animals↗
PubMed2006

Induction and specification of cranial placodes.

Cranial placodes are specialized regions of the ectoderm, which give rise to various sensory ganglia and contribute to the pituitary gland and sensory organs of the vertebrate head. They include the adenohypophyseal, olfactory, lens, trigeminal, and profundal placodes, a series of epibranchial placodes, an otic placode, and a series of lateral line placodes. After a long period of neglect, recent years have seen a resurgence of interest in placode induction and specification. There is increasing evidence that all placodes despite their different developmental fates originate from a common panplacodal primordium around the neural plate. This common primordium is defined by the expression of transcription factors of the Six1/2, Six4/5, and Eya families, which later continue to be expressed in all placodes and appear to promote generic placodal properties such as proliferation, the capacity for morphogenetic movements, and neuronal differentiation. A large number of other transcription factors are expressed in subdomains of the panplacodal primordium and appear to contribute to the specification of particular subsets of placodes. This review first provides a brief overview of different cranial placodes and then synthesizes evidence for the common origin of all placodes from a panplacodal primordium. The role of various transcription factors for the development of the different placodes is addressed next, and it is discussed how individual placodes may be specified and compartmentalized within the panplacodal primordium. Finally, tissues and signals involved in placode induction are summarized with a special focus on induction of the panplacodal primordium itself (generic placode induction) and its relation to neural induction and neural crest induction. Integrating current data, new models of generic placode induction and of combinatorial placode specification are presented.

Animals↗
PubMed1991

Induction kinetics of RNA and proteins in exponentially growing organisms.

A mathematical model of the induction kinetics of RNAs and proteins in exponentially growing organisms is derived, and the cellular concentrations of the induced macromolecules at a given time after induction are related to three parameters: the fraction of the synthesis of these macromolecules in total synthesis, the half life of the inducible macromolecules, and the generation time of the organisms. The model predicts that the concentrations of the inducible macromolecules reach one half of the maximum induction level within one generation time after the onset of the induction. The model also predicts that induction curves of proteins are parabolic when their mRNAs are short-lived, but sigmoid when they are stable. Observed induction curves of beta-galactosidase in Escherichia coli cells fit in the theoretical induction curves.

Enzyme Induction↗
PubMed2001

Signaling pathways leading to the induction of ornithine decarboxylase: opposite effects of p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitors.

Treatment of serum-starved, human ECV304 cells with histamine or ATP elicited a transient induction of ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis, to an extent similar to that provoked by phorbol myristate acetate or serum re-addition. All these agents also provoked an increase in active phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK. The involvement of p44/42 MAPK and p38 MAPK in the induction of ODC was investigated by using selective inhibitors. U0126 and PD98059, two specific p44/42 MAPK kinase inhibitors, prevented the induction of ODC elicited by any stimulus employed, whereas SB203580 and SB202190, which are widely used as p38 MAPK inhibitors, enhanced ODC induction in a way that appeared dependent on p44/42 MAPK activation. By using inhibitors of other key signaling proteins that may lead to activation of p44/42 MAPK, we provide evidence that protein kinase C, but not phosphoinositide 3-kinase, is involved in histamine-stimulated ODC induction. These results show that the p44/42 MAPK pathway, but not p38 MAPK, is essential for ODC induction stimulated either by agonists of G-protein-coupled receptors, phorbol esters, or serum, and suggest that the inhibition of ODC induction may be an important event in the antiproliferative response to p44/42 MAPK pathway inhibitors.

Adenosine Triphosphate↗
PubMed2001

Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures.

Numerous xenobiotics are capable of inducing their own metabolism and by enzyme induction can also lead to enhanced biotransformation of other xenobiotics. In this project, we examined the influence of pyrethroids (permethrin, cypermethrin, and fenvalerate) on the expression and activity of the phenobarbital (PB)-inducible cytochrome P450 2B1 isoform (CYP2B1) in primary rat hepatocyte cultures. Incubation of hepatocyte cultures with pyrethroids resulted in a marked CYP2B1 induction. Among the tested pyrethroids, permethrin elicited the most pronounced induction of CYP2B1 mRNA, which exceeded maximal induction achieved by PB at concentrations approximately 10-fold higher. Furthermore, permethrin induced CYP3A1 mRNA expression, while the expression of the CYP1A1 isoform, which in vivo is not responsive to PB treatment, was not significantly affected by pyrethroids. Permethrin-dependent enhancement of CYP2B1 and CYP3A1 mRNA expression was repressed by the hepatotrophic cytokine epidermal growth factor, which is known to also inhibit PB-dependent induction of CYP2B1. Several metabolites of permethrin formed by hepatocytes (3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid) were ineffective in inducing CYP2B1 mRNA. Furthermore, permethrin stimulated the expression of the luciferase reporter gene under control of the CYP2B1 promoter (comprising the PB-responsive enhancer module) in transiently transfected primary hepatocyte cultures. Thus, permethrin-stimulated gene expression occurred on the transcriptional level. Taken together, these results indicate that the pyrethroid permethrin is a PB-like inducer. Due to its superior potency in induction, permethrin appears as a useful substance for mechanistic studies to elucidate the mechanism of enzyme induction by phenobarbital.

Animals↗