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PubMed1997

Protein kinase C is required for induction of 2',5'-oligoadenylate synthetases.

Induction of the p40/46 and p69/71 isoforms of the 2',5'-oligoadenylate (2-5A) synthetase by interferon-alpha (IFN-alpha) is variable among six different Burkitt lymphoma cell lines with Ramos cells expressing among the highest levels of these enzymes. Inhibitors of protein kinase C (PKC) block induction of mRNAs encoding both isoforms; however, induction of the p69/71 isoform is more sensitive to these inhibitors. Down-regulation of PKC by prolonged treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) also blocks induction of 2-5A synthetase mRNAs and decreases both constitutive and IFN-alpha-induced enzymatic activity. Cotreatment of cells with TPA and IFN-alpha increases induction of 2-5A synthetase mRNAs above that seen in cells treated with IFN-alpha alone. IFN-alpha does not directly activate PKC-alpha or PKC-delta, the two most abundant PKC isoforms present in Ramos cells, suggesting that PKC activation by another signaling pathway is necessary for maximal induction of 2-5A synthetases by IFN-alpha.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Synergistic induction of cytochrome P450 by ethanol and isopentanol in cultures of chick embryo and rat hepatocytes.

The purpose of this study was to investigate whether isopentanol, the most abundant higher chain alcohol in alcoholic beverages, contributes to induction of different forms of hepatic P450s associated with consumption of these beverages. We have previously reported that ethanol and isopentanol each induce P450 2H1/2 in cultured chick hepatocytes and that ethanol induced P450 2B1/2, as well as P450 2E, in cultured rat hepatocytes. Here we investigated the induction of P450 by isopentanol alone and in combination with ethanol in cultured chick and rat hepatocytes. The forms of induced P450 were identified both enzymatically and immunochemically. In cultured chick hepatocytes, both isopentanol and ethanol induced P450 2E, but combined treatment with these alcohols had no greater effect than treatment with ethanol alone. In cultured rat hepatocytes, isopentanol alone did not induce P450 2E or 2B1/2 and had no effect on the ethanol-mediated induction of P450 2E. However, isopentanol combined with ethanol caused a synergistic induction of P450 2B1/2 in cultured rat hepatocytes and an additive to synergistic induction of P450 2H1/2 in cultured chick hepatocytes. The levels of enzyme activities induced by the combined alcohol treatment approached those induced by potent barbiturates. The results suggest that the pentanols in alcoholic beverages may be responsible for a barbiturate-like induction of P450 in hepatocytes.

Animals↗
PubMed1997

A multicompartment geometric model of the liver in relation to regional induction of cytochrome P450s.

A geometric, multicompartment model of the liver was developed to examine regional protein induction and to provide model output suitable for predicting the degree of induction in both the whole liver and in specific regions. The model was based on functional hexagonal arrays within the liver. A geometric representation was used to divide these functional units into five zones: a concentric periportal zone, a fenestrated periportal region that interconnects among multiple functional units, and three concentric centrilobular areas, referred to, respectively, as zones 1 through 5. The surface areas (and volumes for hexagonal cylinders) of these live zones were, respectively, 13.5, 25.2, 33.9, 20.3, and 6.8% of the total liver. The pharmacokinetic model for induction had dissociation constants (Kd) and Hill constants (n) for interactions of transcriptional activator-ligand complexes with response elements on DNA. Estimates of regional induction were converted to color intensities to "paint" the two-dimensional liver for a visual comparison with immunohistochemical observations. To obtain sharp moving boundaries of induced areas with increasing dose (as noted in various experiments), n values in each subcompartment must be large. To create realistic total induction curves that are relatively smooth, the differences in Kd values between adjacent subcompartments must be less than fivefold. Because of the high n values, the low-dose induction characteristics predicted with the multicompartment liver model differ significantly from those predicted with a model that considers the liver as a single homogeneous compartment.

Animals↗
PubMed1997

Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation.

A physiologically based pharmacokinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was combined with a five-compartment geometric model of hepatic zonation to predict both total and regional induction of CYP450 proteins within the liver. Three literature studies on TCDD pharmacokinetics and protein induction in female rats were analyzed. In simulating low-dose behavior for mRNA in whole liver and, particularly, in representing immunohistochemical observations, the five-compartment model was more successful than conventional homogeneous one-compartment liver models. The five-compartment liver model was used with the affinity of TCDD for the Ah receptor (AhR) held constant across all the liver (Kb = 0.2 nM). The presumed affinities of the AhR-TCDD complex for TCDD responsive elements in the CYP1A1 (Kd1) and CYP1A2 (Kd2) genes varied between adjacent compartments by a factor of 3. This parameterization leads to predicted 81-fold differences in affinities between the centrilobular and the periportal regions. The affinities used for AhR-TCDD complex binding to TCDD response elements for CYP1A2 in compartment 3 (the midzonal area) ranged from 0.08 to 1.0 nM in the three studies modeled. For CYP1A1 the corresponding dissociation constant in compartment 3 varied from 0.6 to 2.0 nM. In each compartment, the Hill coefficient for induction had to be 4 or greater to match the immunohistochemical results. This multi-compartment liver model is consistent with data on protein and mRNA induction throughout the liver and on the regional distribution of these proteins. No previous model has incorporated regional variations in induction. The PBPK analysis based on the multicompartment liver model suggests that the low-dose behavior for hepatic CYP1A1/CYP1A2 induction by TCDD is highly non-linear.

Animals↗
PubMed1998

Endocrine factors modulate the phenobarbital-mediated induction of cytochromes P450 and phase II enzymes in a similar strain-dependent manner.

Phenobarbital (PB)-mediated induction of five forms of cytochrome P450 (CYP2B1, CYP2B2, CYP3A1, CYP2A1, and CYP2C6) and epoxide hydrolase is highly suppressed, at the transcriptional level, in Wistar Furth (WF) relative to Fischer 344 (F344) female rats. Either hypophysectomy or thyroid hormone depletion by methimazole largely reverses the suppression in WF animals. Here we show that this strain-dependent polymorphism and unusual endocrine regulation extend to PB induction of phase II enzymes UGT2B1 uridine diphosphate-glucuronosyl transferase (UDPGT), PB-inducible aldehyde dehydrogenase (ALDH), and glutathione transferases Ya1 and Ya2 (GSTYa1 and GSTYa2). UDPGT, ALDH, GSTYa1, and GSTYa2 had mRNA levels induced by PB in a similar strain-dependent manner (F344 > WF). The extent to which mRNA induction was favored in female F344 relative to female WF was gene dependent (UDPGT 5 x; ALDH 15 x; GSTYa1 2 x; GSTYa2 3-5 x). Again, thyroid suppression by methimazole treatment selectively enhanced mRNA induced levels in female WF animals to remove much of the strain difference. Since thyroid hormone action is linked to fatty acid (FA) homeostasis, we tested the possibility that FAs participated in this endocrine polymorphism by using three isocaloric diets: low fat (LFD), polyunsaturated fatty acid (PUFAD), or saturated fatty acid (SFAD). The LFD suppressed PB-induction of CYP mRNA and protein in WF but not F344 rats. This had no parallel in phase II mRNA induction, possibly indicating that FA and thyroid hormone effects are uncoupled. We conclude that the PB-response mechanism for induction of multiple P450 and phase II genes share a pathway that has as a common feature the linkage between chemical stimulation and thyroid hormone suppression that is seen in female WF relative to female F344 rats but not in male rats.

Animals↗
PubMed1979

Glucocorticoid induction of tyrosine aminotransferase in cultured cells.

For over a decade, tyrosine aminotransferase induction in tissue culture cells has been a useful model system in which to study glucocorticosteroid action. In the 1960s, the establishment in culture of rat hepatomas expressing the inducible enzyme, already known to be induced in liver in vivo, provoked a wide-ranging series of experiments. The data from these experiments have provided considerable information regarding the mechanism of action of steroids. These include the fundamental facts that the steroids act directly on the induced cell in unmetablized form, that removal of steroid results in deinduction, that induction does not require DNA synthesis or massive changes in RNA synthesis, and that cytoplasmic receptor occupancy by active steroids correlates closely with the steroids' ability to affect inductions. Studies in tissue culture cells have led to the analysis of transcriptional and posttranscriptional models attempting to explain enzyme induction. The effects on enzyme induction of nonsteroid hormones and other factors have been studied through the use of tissue culture cells. Finally, cells and clones of cell variants are being used to study enzyme induction, through biochemical analysis and cell genetic approaches, including somatic cell hybridization.

Animals↗
PubMed1982

Progressive induction of beta-glucuronidase in individual kidney epithelial cells.

The magnitude and kinetics of beta-glucuronidase induction in mouse kidney are determined by a cis-acting regulatory gene, Gus-r, that is closely linked to the enzyme structural gene. The accumulation of beta-glucuronidase mRNA during induction is much slower than the turnover time of the mRNA, suggesting progressive acquisition of mRNA synthesizing capacity during induction. Counts of the numbers of induced cells present at various times of induction in strains carrying three different alleles of Gus-r show that all potentially responsive cells respond immediately. The level of induction is progressive in individual cells and does not involve continued recruitment of new cells into the induced population. It appears that during induction each chromosome becomes progressively more active in directing the synthesis of beta-glucuronidase.

Animals↗
PubMed1995

Induction of beta-lactamase by cefoxitin in anaerobic intestinal microflora.

Beta-lactamases produced by two anaerobic bacterial strains, Bacteroides ovatus Ax34:1 and Clostridium butyricum NBL3, were shown to be significantly inducible under anaerobic conditions in subinhibitory concentrations of cefoxitin. The induction ratio of beta-lactamase production for Bacteroides ovatus was 2.6 and for Clostridium butyricum 1.6. Incubation of faecal samples with different concentrations of cefoxitin did not result in any induction of beta-lactamase production. When adding a highly inducible aerobic strain (Citrobacter freundii F72:6, induction ratio of 26.5 in broth culture) to faecal samples, an induction ratio of 4.5 was reached. Faeces seem to inhibit beta-lactamase induction in aerobic and anaerobic bacteria. The inducible enzymes produced by the anaerobic strains did not have the same properties as beta-lactamases from aerobic inducible strains, according to substrate profiles and inhibition studies. The results of the present study indicate that increased levels of beta-lactamases in the normal intestinal microflora, which often are observed after administration of beta-lactam agents, are probably due to selection of stably derepressed mutants rather than to induction of beta-lactamase production.

Anti-Bacterial Agents↗
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↗
PubMed1993

Transient induction of cytochrome P450 1A1 mRNA by culture medium component in primary cultures of adult rat hepatocytes.

Because the metabolic environment can alter gene expression in cultured cells, we examined the effects of change of medium on the levels of several cytochrome P450 mRNAs in primary cultures of rat hepatocytes maintained on Matrigel. The amounts of P450 1A2, 2B1/2, or 3A1 mRNA were unaffected by changing the medium. In contrast, P450 1A1 mRNA levels were increased 1 to 2 h after media change, reached maximum levels by 6 h, and declined to baseline by 24 h. Supplementing day-old media with components of the medium revealed that only addition of amino acids resulted in 1A1 mRNA induction. From the results of direct additions and omissions, we showed that tryptophan, but not histidine, was largely responsible for the 1A1 mRNA induction. Moreover, mild photoactivation of the tryptophan resulted in a substantially increased magnitude of 1A1 mRNA induction. The time course for 1A1 mRNA induction by treatment with photoactivated tryptophan was identical to that observed after medium change. Treatment of hepatocyte cultures with beta-naphthoflavone, which is metabolized by 1A1, also resulted in a transient 1A1 mRNA induction time-course profile over a 24-h period, whereas treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is relatively stable to metabolic transformation, produced sustained elevations of 1A1 mRNA, suggesting that the transient response to tryptophan also may involve metabolism of the inducer. Our results extend previous data showing that oxidized products of tryptophan induce 1A1, and suggest that the transient nature of the induction may be due to elimination of the activated tryptophan molecule.

Animals↗
PubMed1981

Catabolite repression during single and multiple induction in Escherichia coli.

Intracellular concentration of cAMP regulates the synthesis of enzymes sensitive to catabolite repression. The relationship between the single and multiple induction of beta-galactosidase (EC 3.2.1.23), L-tryptophanase (EC 4.1.99.1), D-serine deaminase (EC 4.2.1.14), L-asparaginase (EC 3.5.1.1) and L-malate dehydrogenase (EC 1.1.1.37) was studied and the effect of cAMP level on the induction in Escherichia coli Crookes (ATCC 8739) was investigated. A varying degree of catabolite repression was observed during induction of individual enzymes induced separately on different energy sources. The synthesis of l-tryptophanase was most sensitive, whereas l-asparaginase was not influenced at all. Exogenous cAMP was found to overcome partially the catabolite repression of beta-galactosidase and D-serine deaminase, both during single induction. The synthesis of l-malate dehydrogenase was negatively influenced by the multiple induction even in the presence of cAMP; on the other hand, the synthesis of l-tryptophanase was stimulated, independently of the level of the exogenous cAMP. Similarly, the activity of L-asparaginase slightly but significantly increased during the multiple induction of all five enzymes; here too the activity increase did not depend on exogenous cAMP.

Asparaginase↗
PubMed1990

Repeated transient hypergonadotropic amenorrhea during pharmacologic induction of multiple follicular development with exogenous gonadotropins.

Human gonadotropins are widely used for induction of ovulation in the treatment of anovulatory infertility and for induction of multiple follicular development (MFD) in in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), and artificial insemination with husband's semen (AIH) programs. Reported is a patient with normal menstrual cycles, who had two episodes of gonadal unresponsiveness to human gonadotropin therapy, followed by transient hypergonadotropic amenorrhea ("resistant ovary" syndrome), during induction of MFD in conjunction with AIH as treatment for unexplained infertility. The first episode occurred during the sixth cycle of a first series of MFD induction with daily intramuscular injections of exogenous gonadotropins. The second episode occurred during the second cycle of a second series of MFD induction with intravenous pulsatile administration of FSH. On both occasions, normalization of endogenous gonadotropin levels and reappearance of ovulatory cycles occurred spontaneously, after two and three months, respectively. A similar mechanism could occur in the failures of MFD induction observed in IVF programs.

Adult↗
PubMed1997

Short historical survey of pattern formation in the endo-mesoderm and the neural anlage in the vertebrates: the role of vertical and planar inductive actions.

After some introductory remarks about vertical versus horizontal inductive interactions and about planar versus homoiogenetic induction, the author discusses: a) the historical development of the more recently studied endo-mesoderm induction in the Urodeles and in the anuran Xenopus laevis, b) the possible causal relationship between endo-mesoderm induction and the initiation of the gastrulation process, and c) the older history of the regional neural induction as initially studied in the Urodeles and only recently analysed in the anuran Xenopus laevis. The essential vertical interaction in the neural induction process both in urodelian and in anuran amphibians is emphasized.

Amphibians↗
PubMed1994

Comparison of CYP1A1 induction and genotoxicity in vitro as indicators of potentially harmful effects of environmental samples.

Cytochrome P450IA1 (CYP1A1) induction of Hepa-1 mouse and H4IIE rat hepatoma cell lines was compared using selected environmental samples. The results were in agreement for both cell lines: no induction was observed for the fly ash extract from peat combustion, an intermediate induction was found for the fly ash extract from biosludge combustion, and a strong induction was detected for natural peat extract. However, Hepa-1 responded to the samples more sensitively than did H4IIE: the half maximal induction (ED50) values for Hepa-1 were smaller than those for H4IIE. In a bacterial DNA repair assay without metabolic activation and in a mammalian sister chromatid exchange test in the presence of metabolic activation the samples were virtually non-genotoxic. Thus the CYP1A1-inducing potency and genotoxicity of the samples were not correlated. In light of these results, the CYP1A1 induction test might be a useful addition to conventional genotoxicity tests, which may fail to detect potentially harmful compounds/mixtures.

Animals↗
PubMed2004

Results of an organ preservation protocol with induction chemotherapy and radiotherapy in patients with locally advanced laryngeal carcinoma.

An alternative treatment in patients with advanced laryngeal carcinoma who are candidates for total laryngectomy is induction chemotherapy and radical radiotherapy in an organ preservation approach. We conducted a study to evaluate results of this treatment in patients with locally advanced laryngeal carcinoma, candidates for total laryngectomy, who were treated at a single institution between 1985 and 1997. During the study period, 224 began treatment with induction chemotherapy. Induction chemotherapy consisted of three cycles of cisplatin and 5-fluoruracil in the majority of cases. Four patients died as a consequence of complications associated with chemotherapy treatment. Subsequent treatment consisted of total laryngectomy in 79 patients and radical radiotherapy in 141. After radical radiotherapy, local control for patients who achieved a complete response after induction chemotherapy was 74%, significantly better than 57% in patients with a non-complete response (P=0.04). Considering the initial group of 224 patients, the frequency of organ preservation was 39%. Considering only the patients treated with induction chemotherapy and radiotherapy, the organ preservation frequency was 62%. In a multivariate study, only the response after induction chemotherapy was significantly related to organ preservation.

Antineoplastic Agents↗
PubMed1984

Colchicine inhibition of insulin induction of stearoyl-CoA desaturase and fatty acid synthetase in cultured avian liver explants.

Chicken embryo liver explants cultured in chemically defined medium in the absence of serum provide a unique system to probe into the mechanism of insulin induction of lipogenic enzymes. Colchicine at concentrations of 0.2 and 1 microM in the culture medium caused inhibition of insulin induction of stearoyl-CoA desaturase and fatty acid synthetase by 50 and 90%, respectively. As measured by immunochemical techniques, the inhibition of the induction of these two enzyme systems resulted from the decreased content of the delta 9-terminal desaturase component of the stearoyl-CoA desaturase and the fatty acid synthetase. Colchicine, however, had no effect on the general protein synthesis, nor did it affect the malic enzyme, which is induced by triiodothyronine but not by insulin. Also, colchicine had no influence on the binding of 125I-insulin to isolated plasma membrane. Pretreatment of liver explants with insulin for 0.5-1 h and subsequent incubation in insulin-free media for 48 h resulted in induction of the desaturase and fatty acid synthetase. However, inclusion of colchicine in the media for 3 h subsequent to the treatment with insulin completely abolished the inductive effect of insulin, suggesting that colchicine affects events occurring subsequent to insulin binding to the cell surface membranes. Since lumicolchicine, an inactive isomer of colchicine, had no effect on insulin action, it is suggested that the inhibition of insulin induction of the desaturase and synthetase is related to the depolymerizing action of colchicine. Therefore, in eliciting long-term responses to insulin, microtubular integrity of the cell may be required for the transfer of a putative from cell surface insulin receptor to intracellular sites.

Animals↗
PubMed1992

Phorbol ester-mediated suppression of cytochrome P450 Cyp1a-1 induction in murine skin: involvement of protein kinase C.

Epidermal 7-ethoxyresorufin O-deethylase (EROD) activity was elevated greater than 100-fold within 4 to 7 h of topical treatment of SENCAR mice with 100 nmol dibenz[a,c]anthracene (DB[a,c]A). Treatment of skin with 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) 2 to 8 h prior to DB[a,c]A application suppressed induction by 80%. Suppression was dose-dependent over the range of 0.01 to 5 micrograms TPA (ID50 approximately 0.6 nmol). EROD activities in normal and TPA-treated epidermis paralleled steady state P450 CYP1A1 mRNA content. Analogs of TPA incapable of activating or down-regulating protein kinase C (PKC) did not suppress induction. Pretreatment of skin with sn-1,2-didecanoylglycerol, an activator of PKC which causes translocation but no down-regulation, did not suppress EROD induction. However, induction was suppressed by chrysarobin, an anthralin analog that causes PKC down-regulation in the absence of prior activation. These studies suggest that PKC participates in the processes associated with Cyp1a-1 induction and that TPA effects Cyp1a-1 induction through its down-regulation of PKC.

Acetone↗
PubMed1985

Effects of alpha-difluoromethylornithine on polyamine biosynthesis and tyrosine hydroxylase induction in the adrenal gland of the rat subjected to stress or apomorphine.

Ornithine decarboxylase (ODC) and tyrosine hydroxylase (TH), the first enzymes in the polyamine and catecholamine biosynthetic pathways, respectively, are induced in the adrenal gland of the rat through the application of stressors or dopamine agonists. In the present work, following exposure of rats to cold, application of bodily restraint, or administration of apomorphine (APM), adrenal putrescine increased in proportion to the induction of ODC. Spermidine content increased by 60% after APM and about 30% after immobilization. Spermine was unaffected. To test whether the increases of ODC (and polyamines) are necessary to the slower and later induction of TH, induction of ODC in vivo was undertaken. alpha-Difluoromethylornithine (alpha-DFMO), an irreversible inhibitor of ODC, given orally or subcutaneously, almost completely abolished the induction of ODC by APM or immobilization, and inhibited the increase of putrescine in both cases, but did not affect spermidine after APM. Repeated administration of alpha-DFMO over several days did not affect the induction of adrenal TH. The results question whether increases of adrenal ODC activity and of putrescine are essential for the induction of TH in that gland.

Adrenal Glands↗