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PubMed2006

Competing roles of aldo-keto reductase 1A1 and cytochrome P4501B1 in benzo[a]pyrene-7,8-diol activation in human bronchoalveolar H358 cells: role of AKRs in P4501B1 induction.

Benzo[a]pyrene (BP) requires metabolic activation to electrophiles to exert its deleterious effects. We compared the respective roles of aldo-keto reductase 1A1 (AKR1A1, aldehyde reductase) and P4501B1 in the formation of BP-7,8-dione and BP-tetrols, respectively, in intact bronchoalveolar cells manipulated to express either enzyme. Metabolite formation was confirmed by HPLC/MS and quantitatively measured by HPLC/UV/beta-RAM. In TCDD-treated H358 cells (P4501B1 expression), the anti-BPDE hydrolysis product BP-tetrol-1 increased over 3-12 h to a constant level. In H358 AKR1A1 transfectants, formation of BP-7,8-dione was elevated for 3-12 h but significantly decreased after 24 h. Interestingly, BP-tetrols were also detected in AKR1A1 transfectants even though they do not constitutively express P4501A1/P4501B1 enzymes. Northern and Western blotting confirmed the induction of P4501B1 by BP-7,8-dione in parental cells and the induction of P4501B1 by BP-7,8-diol in AKR1A1-transfected cells. P4501B1 induction was blocked in AKR1A1 transfectants by the AKR1A1 inhibitor (sulfonylnitromethane), the o-quinone scavenger (N-acetyl-l-cysteine), or the cytosolic AhR antagonist (diflubenzuron). Attenuation of P4501B1 induction in these cells was verified by measuring a decrease in BP-tetrol formation. Our studies show that the formation of BP-7,8-dione by AKR1A1 in human bronchoalveolar cells leads to an induction of P4501B1 and that a functional consequence of this induction is elevated anti-BPDE production as detected by increased BP-tetrol formation. Therefore, the role of AKR1A1 in the activation of BP-7,8-diol is bifunctional; that is, it directly activates BP-7,8-diol to the reactive and redox-active PAH o-quinone (BP-7,8-dione) and it indirectly trans-activates the P4501B1 gene by generating the aryl hydrocarbon receptor (AhR) ligand BP-7,8-dione.

Alcohol Oxidoreductases↗
PubMed2000

Induction of UDP-glucuronosyltransferase by the flavonoids chrysin and quercetin in Caco-2 cells.

PURPOSE: Dietary flavonoids have been reported to be potent inhibitors of drug metabolizing enzymes. In the present study we examined the inducing effect of three of these compounds, chrysin, quercetin and genistein, on UDP-glucuronosyltransferase (UGT) in the human intestinal cell line Caco-2. METHODS: The induction of UGT by flavonoid pretreatment was studied both in the intact cells and cell homogenates, measured as the glucuronidation of chrysin, and by immunoblot analysis of the UGT 1A protein. RESULTS: Exposure of Caco-2 cells to 50 microM chrysin resulted in a 3.8-fold increase in chrysin glucuronidation in intact cells (p < 0.0001) with a 38% decrease in sulfation (p < 0.01). In the cell homogenate the induction was much larger, 14-fold. The induction was slow to develop with maximum induction after 3-4 days. Interestingly, the isoflavonoid genistein was without effect. Immunoblot analysis of Caco-2 cell microsomes with a UGT1A subfamily-selective antibody showed a markedly increased band at about 59 kDa, consistent with induction of one or more UGT1A isoforms. A 5-week exposure of Caco-2 cells to low concentrations (10 microM) of chrysin or quercetin also showed markedly increased glucuronidation activity. CONCLUSIONS: Diet-mediated induction of intestinal UGT may be important for the bioavailability of carcinogens and other toxic chemicals as well as therapeutic drugs.

Caco-2 Cells↗
PubMed2000

Generic human menopausal gonadotropin (hMG) in place of more costly follicle-stimulating hormone (FSH) for routine ovulation induction.

PURPOSE: A large part of infertility treatment involves the use of exogenous gonadotropins. The last decade has seen a progressive switch from human menopausal gonadotropin (hMG), the original gonadotropin product, to progressively more costly products, primarily or exclusively containing follicle-stimulating hormone (FSH). Though obviously at least in part driven by marketing efforts of pharmaceutical companies, this switch has received relatively little scrutiny despite its obvious cost implications. We therefore investigated whether a switch back to a generic or less costly hMG-driven ovulation induction protocol would affect patient outcome after ovulation induction and, by implications, with other assisted reproductive technologies. METHODS: We prospectively studied clinical pregnancy rates in a large number of consecutive ovulation induction cycles in a well-defined patient population (group 1) which, after October of 1997, had been switched from a predominantly FSH to an hMG-driven protocol, based on an institutional formulary change. Until a transition period (between July and September 1997), this patient population had been on a primarily FSH-driven protocol (between July 1996 and June 1997). In parallel, we evaluated a second patient population (group 2), which was managed by the same physicians outside of formulary requirements and remained almost exclusively on principally FSH-driven ovulation induction cycles. RESULTS: FSH- and hMG-driven ovulation induction protocols did not differ in pregnancy outcome during the prospective study period. Group 1 patients, however, demonstrated a significant increase in pregnancy rates after the switch from FSH to hMG stimulation had taken place (P = 0.02), while group 2 patients demonstrated no change in pregnancy rate during the same time period. CONCLUSIONS: Generic hMG products do not adversely affect pregnancy rates in comparison to more costly FSH products in routine ovulation induction cycles and should be considered an appropriate alternative to more expensive FSH products.

Female↗
PubMed1988

Protein kinase C mediates neural induction in Xenopus laevis.

Inductive cell interactions are essential in early embryonic development, but virtually nothing is known about the molecular mechanisms involved. Recently factors resembling fibroblast growth factor and transforming growth factor-beta were shown to be involved in mesoderm induction in Xenopus laevis, suggesting that membrane receptor-mediated signal transduction is important in induction processes. Here we report direct measurements of protein kinase C (PKC) activity in uninduced ectoderm, and in neuroectoderm shortly after induction by the involuting mesoderm, in Xenopus laevis embryos. Membrane-bound PKC activity increased three to fourfold in the induced neuroectoderm while the cytosolic PKC activity was decreasing, indicating that PKC activity was translocated during neural induction. A similar time- and dose-dependent translocation of activity was seen after incubation with the PKC activator 12-O-tetradecanoyl phorbol-13-acetate, which also induced neural tissue in competent ectoderm, suggesting that PKC is involved in the response to the endogenous inducing signal during neural induction.

Animals↗
PubMed2003

Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy.

Induction chemotherapy of non-small-cell lung cancer (NSCLC) stage III with gemcitabine and cisplatin for downstaging of the tumour with the aim for further treatment with ionising radiation is one of the treatments for lung cancer patients. The purpose of this study was to investigate the influence of the waiting time for radiotherapy, that is, the interval between induction chemotherapy and radiotherapy, on the rate of tumour growth for patients with NSCLC. Interval times between the end of induction chemotherapy and date of diagnostic CT, planning CT and first day of radiotherapy were determined for 23 patients with NSCLC. Increase in gross tumour volume was measured for 18 patients by measuring the dimensions of the primary tumour and lymph node metastases on the diagnostic CT after induction chemotherapy and on the CT used for radiotherapy planning. For each patient, the volume doubling time was calculated from the time interval between the two CTs and ratio of the gross volumes on planning CT and diagnostic CT. The mean time interval between end of chemotherapy and day of diagnostic CT was 16 days, and till first day of radiotherapy 80.3 (range 29-141) days. In all, 41% of potentially curable patients became incurable in the waiting period. The ratio of gross tumour volumes of the two CTs ranged from 1.1 to 81.8 and the tumour doubling times ranged from 8.3 to 171 days, with a mean value of 46 days and median value of 29 days. This is far less than the mean doubling time of NSCLC in untreated patients found in the literature. This study shows that in the time interval between the end of induction chemotherapy and the start of radiotherapy rapid tumour progression occurs as a result of accelerated tumour cell proliferation: mean tumour doubling times are much shorter than those in not treated tumours. As a consequence, the gain obtained with induction chemotherapy with regard to volume reduction was lost in the waiting time for radiotherapy. We recommend diminishing the time interval between chemo- and radiotherapy to as short as possible.

Adult↗
PubMed2006

Docetaxel-based induction therapy prior to radiotherapy with or without docetaxel for non-small-cell lung cancer.

This trial aimed to assess the feasibility and tumour control of concurrent chemoradiotherapy or radiotherapy alone after docetaxel-based induction chemotherapy in locally advanced non-small-cell lung cancer (NSCLC). Patients with stage IIIA/IIIB NSCLC received two 21-day cycles of induction chemotherapy with docetaxel (85 mg m(-2), day 1) plus cisplatin (40 mg m(-2), days 1 and 2). Patients without disease progression on day 43 were randomised to radiotherapy (2 Gy for 5 days week(-1); total 60 Gy) alone or with docetaxel 20 mg m(-2) once weekly every 6 weeks. Of 108 patients who received induction chemotherapy, 104 were evaluable for response. After induction chemotherapy, the overall response rate (ORR) was 44%; 91 (88%) patients had no disease progression and 89 were subsequently randomised to local treatment. After randomised therapy, the ORR was 53% (chemoradiotherapy 58%; radiotherapy 48%). Median survival and time to progression were 14.9 and 7.8 months, respectively, for chemoradiotherapy and 14.0 and 7.5 months, respectively, for radiotherapy. The most common toxicities during induction chemotherapy and randomised therapy were grades 3-4 neutropenia and grade 3 lymphocytopenia, respectively. Docetaxel-cisplatin induction therapy followed by concurrent docetaxel and thoracic radiotherapy is a feasible treatment option, showing good clinical activity and tolerability, for locally advanced NSCLC.

Adolescent↗
PubMed2001

Potentiation of cytokine induction of group IIA phospholipase A(2) in rat mesangial cells by ATP and adenosine via the A2A adenosine receptor.

1. In rat mesangial cells extracellular nucleotides were found to increase arachidonic acid release by a cytosolic phospholipase A(2) through the P2Y(2) purinergic receptor. 2. In this study we investigated the effects of ATP and UTP on interleukin-1ss (IL-1ss)-induced mRNA expression and activity of group IIA phospholipase A(2) (sPLA(2)-IIA) in rat mesangial cells. 3. Treatment of cells for 24 h with extracellular ATP potentiated IL-1ss-stimulated sPLA(2)-IIA induction, whereas UTP had no effect. 4. We obtained the following evidence that the P2Y(2) receptor is not involved in the potentiation of sPLA(2)-IIA induction: (i) ATP-gamma-S had no enhancing effect; (ii) suramin, a P(2) receptor antagonist, did not inhibit ATP-mediated potentiation; (iii) inhibition of degradation of extracellular nucleotides by the 5'-ectonucleotidase inhibitor AOPCP did not enhance sPLA(2)-IIA induction and (iv) adenosine deaminase treatment completely abolished the ATP-mediated potentiation of sPLA(2)-IIA induction. 5. In contrast, treatment of mesangial cells with adenosine or the A2A receptor agonist CGS 21680 mimicked the effects of ATP in enhancing IL-1ss-stimulated sPLA(2)-IIA induction, whereas the specific A2A receptor antagonist ZM 241385 completely abolished the potentiating effect of ATP or adenosine. 6. The protein kinase A inhibitor Rp-8-Br-cyclic AMPS dose-dependently inhibited the enhancing effect of ATP or adenosine indicating the participation of an adenosine receptor-mediated cyclic AMP-dependent signalling pathway. 7. These data indicate that ATP mediates proinflammatory long-term effects in rat mesangial cells via its degradation product adenosine through the A2A receptor resulting in potentiation of sPLA(2)-IIA induction.

5'-Nucleotidase↗
PubMed1980

Haem control in experimental porphyria. The effect of haemin on the induction of delta-aminolaevulinate synthase in isolated chick-embryo liver cells.

2-Allyl-2-isopropylacetamide-mediated induction of hepatic porphyria was studied in isolated chick-embryo liver cells. Increased delta-aminolaevulinate synthase activity occurred within 1h of induction and continued to increase for 8h. Protoporphyrins synthesized during this time accumulated to a concentration 10-fold greater than that in the control. Removal of 2-allyl-2-isopropylacetamide from the cells by washing at 3h immediately inhibited further increases in delta-aminolaevulinate synthase synthesis. However substitution of 2-allyl-2-isopropylacetamide at 3h by deferoxamine methane-sulphonate, an inhibitor of haem synthesis, allowed continued delta-aminolaevulinate synthase induction at an unaltered rate, even though this agent did not, by itself, induce enzyme synthesis. Exogenously added haemin was shown completely to inhibit 2-allyl-2-isopropylacetamide-mediated delta-aminolaevulinate synthase induction at concentrations as low as 20nm, a value that is less than the reported physiological one. The duration of inhibition was dependent on the concentration of added haemin and was followed by a period of delta-aminolaevulinate synthase synthesis at a rate similar to that of the control. These data are consistent with the hypothesis that delta-aminolaevulinate synthase synthesis is regulated by the concentration of intracellular haem and that induction is initiated by 2-allyl-2-isopropylacetamide-mediated destruction of haem. Induction of delta-aminolaevulinate synthase was shown to be dependent on both RNA and protein synthesis, and a study of the comparative effects of cordycepin, cycloheximide and haem has shown that, at haemin concentrations up to 50nm, the inhibition of delta-aminolaevulinate synthase synthesis followed kinetics similar to the effect of cordycepin, with no synergism between cordycepin and 50nm-haemin. However, at a haemin concentration of 2mum, the inhibition of delta-aminolaevulinate synthase synthesis followed similar kinetics to the effect of cycloheximide. These data demonstrate the control of delta-aminolaevulinate synthase synthesis by low concentrations of haemin and suggests that the primary effect of haemin is at the level of transcription.

5-Aminolevulinate Synthetase↗
PubMed2004

Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction.

TCDD (2,3,7,8-tetrachlorodibenzo- p -dixoin) induces phase II drug-metabolizing enzyme NQO1 [NAD(P)H:quinone oxidoreductase; EC 1.6.99.2; DT-diaphorase] in a wide range of mammalian tissues and cells. Here, we analysed the molecular pathway mediating NQO1 induction by TCDD in mouse hepatoma cells. Inhibition of protein synthesis with CHX (cycloheximide) completely blocks induction of NQO1 by TCDD as well as the basal expression and induction by phenolic antioxidant tBHQ (2-t-butylbenzene-1,4-diol), implicating a labile factor in NQO1 mRNA expression. The inhibition is both time- and concentration-dependent, requires inhibition of protein synthesis, and occurs at a transcriptional level. Inhibition of NQO1 transcription by CHX correlates with a rapid reduction of the CNC bZip (cap 'n' collar basic leucine zipper) transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) through the 26 S proteasome pathway. Moreover, blocking Nrf2 degradation with proteasome inhibitor MG132 increases the amount of Nrf2 and superinduces NQO1 in the presence of TCDD or tBHQ. Finally, genetic experiments using AhR (aryl hydrocarbon receptor)-, Arnt (aryl hydrocarbon receptor nuclear translocator)- or Nrf2-deficient cells reveal that, while induction of NQO1 by TCDD depends on the presence of AhR and Arnt, the basal and inducible expression of NQO1 by either TCDD or tBHQ requires functional Nrf2. The findings demonstrate a novel role of Nrf2 in the induction of NQO1 by TCDD and provide new insights into the mechanism by which Nrf2 regulates the induction of phase II enzymes by both phenolic antioxidants and AhR ligands.

Animals↗
PubMed1989

Sex-related difference in the inductions by perfluoro-octanoic acid of peroxisomal beta-oxidation, microsomal 1-acylglycerophosphocholine acyltransferase and cytosolic long-chain acyl-CoA hydrolase in rat liver.

Inductions by perfluoro-octanoic acid (PFOA) of hepatomegaly, peroxisomal beta-oxidation, microsomal 1-acylglycerophosphocholine acyltransferase and cytosolic long-chain acyl-CoA hydrolase were compared in liver between male and female rats. Marked inductions of these four parameters were seen concurrently in liver of male rats, whereas the inductions in liver of female rats were far less pronounced. The sex-related difference in the response of rat liver to PFOA was much more marked than that seen with p-chlorophenoxyisobutyric acid (clofibric acid) or 2,2'-(decamethylenedithio)diethanol (tiadenol). Hormonal manipulations revealed that this sex-related difference in the inductions is strongly dependent on sex hormones, namely that testosterone is necessary for the inductions, whereas oestradiol prevented the inductions by PFOA.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed2002

Induction therapy with consensus interferon (CIFN) does not improve sustained virologic response in chronic hepatitis C.

In patients infected with hepatitis C virus (HCV) genotype 1, sustained viral response (SVR) averages 10-40% depending on treatment regime. It has been proposed that high dose daily interferon (IFN) therapy early in therapy (induction dosing) may enhance SVR. In the present study we examined this issue and also assessed whether one could predict SVR and non-SVR, based on viral kinetics during the first month of induction therapy. End of treatment response and SVR was determined in 173 HCV infected patients who were treated with different induction doses of consensus interferon (CIFN) for one month followed by 11 months of standard 9 microg of CIFN thrice weekly (TIW). The second phase decline slope was calculated by log-linear regression on weekly measurements of serum HCV RNA during the first 7-28 days of treatment; rapid viral response (RVR) during the first month of induction dosing was defined as a decline of > 0.3 log copies/mL/week. Overall, SVR occurred in 11% of genotype 1 infected patients and 41% of patients with nongenotype 1. High dose induction therapy did not increase the rate of SVR, in either genotype 1 or genotype 2/3 infected patients. No patient without a RVR during the first month had SVR, while SVR occurred in 55% of the patients with RVR. RVR was the best predictor of SVR using multivariate analysis. These results indicate that induction dosing with CIFN does not improve SVR rates. They also suggest that early viral kinetics during the first month of therapy can predict non-SVR and thus save a patient a year long treatment which is fraught with side-effects and significant cost.

Adult↗
PubMed2001

The Ras-ERK pathway is required for the induction of neuronal nitric oxide synthase in differentiating PC12 cells.

We have studied the role of MAP kinase pathways in neuronal nitric oxide synthase (nNOS) induction during the differentiation of PC12 cells. In nerve growth factor (NGF)-treated PC12 cells, we find nNOS induced at RNA and protein levels, resulting in increased NOS activity. We note that neither nNOS mRNA, nNOS protein nor NOS activity is induced by NGF treatment in cells that have been infected with a dominant negative Ras adenovirus. We have also used drugs that block MAP kinase pathways and assessed their ability to inhibit nNOS induction. Even though U0126 and PD98059 are both MEK inhibitors, we find that U0126, but not PD98059, blocks induction of nNOS protein and NOS activity in NGF-treated PC12 cells. Also, the p38 kinase inhibitor, SB203580, does not block nNOS induction in our clone of PC12 cells. Since the JNK pathway is not activated in NGF-treated PC12 cells, we conclude that the Ras-ERK pathway and not the p38 or JNK pathway is required for nNOS induction in NGF-treated PC12 cells. We find that U0126 is much more effective than PD98059 in blocking the Ras-ERK pathway, thereby explaining the discrepancy in nNOS inhibition. We conclude that the Ras-ERK pathway is required for nNOS induction.

Animals↗
PubMed2001

Remission induction therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines.

Remission induction therapy with vincristine, a corticosteroid, L-asparaginase and an anthracycline has been the mainstay of the initial phase of treatment for childhood acute lymphoblastic leukaemia (ALL) for the past 25 years. The speed and depth of the early response to remission induction therapy has become an important determinant of the intensity of subsequent therapy in many protocols worldwide. Moreover, the detection of significant levels of minimal residual disease at the end of remission induction may have an important bearing on subsequent outcome. Although these clinical observations may reflect, in part, the inherent sensitivity of lymphoblasts to remission induction therapy, the pharmacology of these agents in relation to childhood ALL may also play an important part in early response to therapy. In-vitro studies of human leukaemia cell lines indicate that both the extracellular fluid concentration and duration of exposure to vincristine and anthracyclines are important determinants of cytotoxicity. For L-asparaginase and corticosteroids, the cellular and molecular pharmacological determinants of chemosensitivity have been partially characterized, but further work is needed in this area. The clinical pharmacology of vincristine and L-asparaginase have been well characterized in relation to childhood ALL, and considerable interpatient pharmacokinetic variability exists for these drugs. For corticosteroids and anthracyclines, pharmacology studies are needed in order to fully characterize and understand the factors influencing interpatient pharmacokinetic variability for these agents in relation to childhood ALL. Whereas the relationship between the clinical pharmacology, and potentially important pharmacodynamic effects such as asparagine depletion, has been well characterized for therapy with L-asparaginase, similar studies have yet to be performed for the other drugs that form the mainstay of remission induction therapy for childhood ALL. Therefore, further studies are required to investigate the relative importance of the clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines in the speed and depth of response to remission induction therapy for childhood ALL. Where these have been studied, interindividual differences in the clinical and cellular pharmacology of anticancer agents have been shown to be important determinants of the long-term disease-free survival for children with ALL.

Antibiotics, Antineoplastic↗
PubMed1995

Metallothionein: in vitro induction with zinc and streptozotocin in pancreatic islets of mice.

Recently, this laboratory reported that the antioxidant metallothionein (MT) is constitutively expressed and significantly (p < 0.001) induced with zinc in pancreatic islets in vivo. Therefore, our aim was to study, whether MT can also be induced in vitro. We found that incubation of islets with either zinc sulfate (Zn) or streptozotocin (STZ) resulted in significant (p < 0.001) dose-dependent MT induction. With Zn a maximal induction was obtained with 0.1 mM reaching an induction index of 6.9 in C57BL/6 mice; a significant induction was also obtained in CD-1 mice. With subtoxic concentrations of STZ (2 and 4 mM) a significant induction was obtained in C57BL/6 mice. Thus, our in vivo data have been confirmed in vitro. Current investigations aim to analyse, whether MT induction can protect islets against toxicity mediated by reactive oxygen species (ROS).

Animals↗
PubMed1977

Proof of de novo synthesis of the qa enzymes of Neurospora crassa during induction.

In Neurospora crassa three inducible enzymes are necessary to catabolize quinic acid to protocatechuic acid. The three genes encoding these enzymes are tightly linked on chromosome VII near methionine-7 (me-7). This qa cluster includes a fourth gene, qa-1, which encodes a regulatory protein apparently exerting positive control over transcription of the other three qa genes. However, an alternative hypothesis is that the qa-1 protein simply activates preformed polypeptides derived from the three structural genes. The use of density labeling with D(2)O demonstrated conclusively that the qa enzymes are synthesized de novo only during induction on quinic acid. Native catabolic dehydroquinase (5-dehydroquinate dehydratase; 5-dehydroquinate hydro-lyase, EC 4.2.1.10) (a homopolymer of ca 22 identical subunits) has a density of 1.2790 g/cm(3) as determined by centrifugation in a modified cesium chloride density gradient. Growth in H(2)O followed by induction in 95% D(2)O shifts the density of the enzyme to 1.3130 g/cm(3), indicating de novo synthesis during induction. In the reciprocal experiment, i.e., growth in 80% D(2)O followed by induction in either 95% D(2)O or H(2)O, the densities of catabolic dehydroquinase were 1.3135 and 1.2800 g/cm(3), respectively. Because growth on D(2)O does not affect the density of the H(2)O-induced enzyme, there can be no significant synthesis of catabolic dehydroquinase prior to induction. Similar results were obtained for a second qa enzyme, quinate dehydrogenase (quinate:NAD(+) oxidoreductase, EC 1.1.1.24). Thus, induction of two qa enzymes involves de novo protein synthesis, not enzyme activation or assembly.

Alcohol Oxidoreductases↗
PubMed1979

Manganese and zinc blockade of enzyme induction: studies with microsomal heme oxygenase.

Heme oxygenase (decyclizing) [heme,hydrogen-donor:oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating), EC 1.14.99.3] is greatly induced in the kidney by the administration of nickel or tin. Manganese, when administered simultaneously with nickel or tin in an equimolar amount, substantially inhibited the induction of heme oxygenase. The extent of inhibition was 80% and 98%, respectively. In rats pretreated up to 8 hr with manganese, the level of induction of heme oxygenase by nickel or tin was markedly reduced in a time-dependent fashion. Manganese treatment after the inducing metal was relatively ineffective in preventing the induction of heme oxygenase. Manganese in vitro did not inhibit heme oxygenase in the microsomes isolated from either control or tin-induced rats and in vivo did not increase the rate of catabolism of the induced enzyme. Magnesium was unable to block nickel or tin induction of heme oxygenase. Zinc in equimolar amounts could also substantially reduce the extent of induction of renal heme oxygenase when administered simultaneously with nickel or tin. In addition, simultaneous zinc administration blocked to a considerable extent the induction of hepatic heme oxygenase by nickel, cobalt, or cadmium. These findings indicate the existence of metal-metal interactions that can greatly influence the regulatory mechanism for the induced synthesis of heme oxygenase, the rate-limiting enzyme in heme degradation.

Animals↗
PubMed1990

Persistent induction of cyclooxygenase in p60v-src-transformed 3T3 fibroblasts.

A BALB/c 3T3 cell line infected with the temperature-sensitive Rous sarcoma virus strain LA90 has been used to investigate early, p60v-src-dependent changes in gene expression (protein synthesis). Giant two-dimensional electrophoresis, which can resolve greater than 3000 polypeptides from [35S]methionine-labeled cell lysates, was used to detect the induction of a p72-74 (72-74 kDa) doublet (pI 7.5) after activation of p60v-src at 35 degrees C. Antiserum against cyclooxygenase (prostaglandin synthase or prostaglandin endoperoxide synthase) specifically immunoprecipitated the p72-74 doublet. The p72-74 doublet was also induced by platelet-derived growth factor and by phorbol 12-myristate 13-acetate and was elevated in an NIH 3T3 cell line transformed by wild-type src. Activation of p60v-src caused a persistent increase in p72-74, whereas the effect of the growth factor was transient. These dissimilar kinetics of induction were paralleled by changes in cyclooxygenase activity. Down-regulation of protein kinase C inhibited subsequent induction of cyclooxygenase by phorbol myristate acetate but did not block induction by p60v-src. The glucocorticoid agonist dexamethasone inhibited induction of cyclooxygenase by p60v-src. Although induction of this enzyme may not be directly involved in transformation, the data support the view that oncogenic transformation may result, not from expression of transformation-specific genes, but from persistent changes in the expression of genes normally induced only transiently during passage from the G0 stage of the cell cycle.

Animals↗
PubMed1994

Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo.

An enhanced formation of nitric oxide (NO) due to induction of a calcium-independent (inducible) NO synthase (iNOS) contributes importantly to the cardiovascular failure caused by bacterial endotoxin. Repeated challenges with small doses of endotoxin result in tolerance to both peripheral vascular failure and death caused by subsequent injection of a higher dose of endotoxin. Here we investigate whether tolerance to endotoxin is associated with a lack of induction of iNOS in vivo and whether endogenous glucocorticoids play a role in the development of endotoxin tolerance. In anesthetized rats, i.v. administration of Escherichia coli endotoxin [lipopolysaccharide (LPS); 2 mg.kg-1] resulted in a prolonged decrease in mean arterial blood pressure (MAP) and hyporeactivity to the contractile responses elicited by norepinephrine (NE; 10 nM) in aortic rings ex vivo. Hyporeactivity to NE was partially reversed by NG-nitro-L-arginine methyl ester (0.3 mM) in vitro, suggesting that an enhanced formation of NO contributes to this hyporeactivity. There was a substantial increase in the activity of iNOS in the lung 3 h after i.v. injection of LPS (0.2 +/- 0.1 to 6.6 +/- 0.6 pmol.mg-1.min-1; n = 5; P < 0.01). Rats injected i.p. with LPS (0.5 mg.kg-1) for 4 consecutive days became tolerant to an i.v. injection of LPS (2 mg.kg-1) in that both hypotension and vascular hyporeactivity to NE were significantly attenuated. Moreover, in these endotoxin-tolerant rats, the induction of iNOS by LPS in the lung was attenuated by 63% +/- 6%. Injection of LPS caused a 9-fold increase in plasma corticosterone (CCS) levels within 2 h and CCS levels remained significantly elevated 6 and 24 h after LPS. Animals rendered tolerant to endotoxin by administration of a low dose of LPS (0.5 mg.kg-1, i.p.) for 4 days still had a 6-fold increase in plasma CCS levels 24 h after the last injection of LPS. When endotoxin-tolerant rats were treated with the glucocorticoid receptor antagonist RU 486 (50 mg.kg-1, p.o. 3 h prior to LPS), there was a restoration of the effects of LPS (2 mg.kg-1, i.v.) in causing hypotension, vascular hyporeactivity to NE, and iNOS induction in the lung. However, in control rats RU 486 enhanced neither the decrease in MAP nor the induction of iNOS in response to LPS (2 mg.kg-1, i.v.). Thus, cardiovascular tolerance to endotoxin is accompanied and explained by reduced induction of iNOS in vivo due to the elevation of endogenous glucocorticoid levels.

Amino Acid Oxidoreductases↗