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PubMed1988

Complete remission in acute promyelocytic leukemia despite persistence of abnormal bone marrow promyelocytes during induction therapy: experience in 34 patients.

Thirty-four patients with acute promyelocytic leukemia (APL) (median age 37 years, range 20 to 69 years) received induction treatment between 1974 and 1985 with cytosine arabinoside (ara-C) and an anthracycline. Bone marrow hypercellularity was present at the time of diagnosis in all patients, although the median peripheral leukocyte count was 2,600/microL. A second course of induction therapy consisting of further ara-C and anthracycline was initiated 15 days after the start of treatment if bone marrow hypocellularity could not be documented. Karyotypic analysis of bone marrow blasts was performed on 15 of 34 patients; 11 of 15 had abnormalities in chromosomes 15 and/or 17. Twenty-nine of 34 (85%) patients had laboratory evidence of disseminated intravascular coagulopathy. Of the 29 patients surviving 14 days, 24 (83%) received a second course of induction therapy. Complete remission was achieved in 25 of 34 (74%) patients, with four of 25 (16%) requiring one course of induction chemotherapy and 21 of 25 (84%) receiving two courses. Bone marrow specimens obtained 15 days after the start of therapy from the 25 patients who eventually attained complete remission showed the continued presence of dysplastic promyelocytes in 21 cases; three specimens were technically inadequate and only one was truly devoid of promyelocytes. Seventeen of 25 (68%) patients still had persistence of abnormal bone marrow promyelocytes seven or more days after the second course of therapy. Patients in complete remission received various forms of postremission therapy. Ten of the 25 (40%) completely responding patients remain alive in continuous complete remission. Neither the absence of bone marrow hypocellularity nor the persistence of dysplastic promyelocytes during induction exerted any influence on the probability for survival. These findings confirm and extend prior reports that complete remission in APL, in contrast to other subtypes of acute nonlymphocytic leukemia (ANLL), can frequently be achieved without bone marrow aplasia. Whether this observation signifies that complete remission in APL is due to leukemic cell differentiation or selective cytotoxicity is unknown. The absence of therapy-induced bone marrow hypoplasia in APL is not an absolute indication of induction failure or a poor ultimate prognosis.

Acute Disease↗
PubMed1985

In vitro induction of human skin ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

A method was developed for the in vitro induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) activity in human skin punch biopsy samples. Addition of TPA to 1 ml serum-free minimum essential medium containing a single 3-mm human skin punch biopsy sample obtained from a surgical specimen resulted in an induction of ODC activity with a peak activity at 5 hours after TPA addition. In vitro induction of human epidermal ODC activity was dependent on the TPA concentration in the medium; about a twofold increase in ODC activity was observed 6 hours after the addition of 0.1 microM TPA, and about a fivefold increase in ODC activity was observed with 1 microM TPA. TPA also caused about a fivefold to sixfold increase in ODC activity in 3-mm skin punch biopsy samples from healthy volunteers. Human skin punch biopsy samples remained responsive to TPA induction of ODC activity even when stored in serum-free medium at 4 degrees C for 24 hours. A similar degree of induction of ODC activity by TPA was observed whether whole unfractionated human epidermis or a soluble epidermal extract was used for ODC assays. Increased ODC activity was the result of the increase in enzymatically active ODC protein, quantitated by a [3H]difluoromethylornithine-binding assay. Thus human skin, like mouse skin, is responsive to TPA for ODC induction.

Amputation, Surgical↗
PubMed1986

Tumor promoter-induced refractory state against ornithine decarboxylase induction by 12-O-tetradecanoylphorbol-13-acetate in mouse epidermis.

More than one application of the potent tumor-promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA), to mouse skin at intervals of more than 48 h led to a larger induction of ornithine decarboxylase (EC 4.1.1.17; ODC) than did a single application. In contrast, at intervals of less than 24 h, the first application of TPA appeared to induce a refractory state; the second application of TPA did not induce ODC. The extent of the inhibitory effect caused by the first application of TPA was dependent on the dose. The abilities of a series of phorbol esters to induce the refractory state correlated with their promoting abilities. However, both mezerein and ethylphenylpropiolate, potent hyperplastic agents with little or no promoting properties, induced the refractory state. On the other hand, pretreatment with TPA caused a refractory effect on ODC induction by mezerein but potentiated ODC induction by ethylphenylpropiolate. The epidermal cells escaped from the refractory state by repeated application of TPA at intervals of 24 h as well as at intervals of twice a week; that is, there was a full induction of ODC activity following a second application within 24 h of a prior application. TPA did not elicit production of detectable ODC-antizyme activity in mouse epidermis. Mixing of a soluble extract from mouse epidermis in the refractory state with that from TPA-stimulated epidermis gave essentially additive ODC activity. Elimination of ODC induction by topical application of retinoic acid or injection of cycloheximide concurrent with the first application of TPA did not restore the ability of a second application of TPA to induce ODC. These results suggest that the refractory effect on ODC induction by TPA does not result from feedback regulation of ODC.

Acetone↗
PubMed1983

Induction of tyrosine aminotransferase activity by concanavalin A in cultured rat hepatoma cells.

Concanavalin (Con A) induced tyrosine aminotransferase activity in cultured rat hepatoma cells (R117-21B). The highest level of the induced enzyme activity was observed at 6 to 8 hr of incubation with Con A, and the activity returned to the control level after 24 hr. This enzyme induction was dose-dependent in the range of 0.5 to 5 micrograms Con A per ml, while at higher concentrations (more than 50 micrograms/ml) the induction was very small or absent. The addition of alpha-methyl-D-mannoside abolished the effect of Con A. A 4 hr incubation of the cells with Con A and a subsequent 2 hr incubation was necessary to yield the maximal induction of tyrosine aminotransferase activity. Simultaneous incubation of the cells with Con A (5 micrograms/ml) and insulin or dexamethasone, induced tyrosine aminotransferase activity to levels higher than each activator alone, and the effect of Con A on the induction of tyrosine aminotransferase activity by dexamethasone was almost an additive. It was concluded that Con A at low concentrations mimics insulin in the induction of tyrosine aminotransferase activity in R117-21B cells, and that the effect of Con A and insulin on the induction of the enzyme is different from the effect of dexamethasone on this process.

Animals↗
PubMed1984

Modulation of rat pineal acetyl-Co A:arylamine N-acetyltransferase induction by alpha adrenergic drugs.

The modulatory effects of alpha adrenergic drugs on the induction of rat pineal acetyl-CoA:arylamine N-acetyltransferase (NAT) activity were characterized using both in vivo and organ culture techniques. Intraperitoneal administration of phenoxybenzamine (POB) to rats was followed by a 2- to 3-fold increase in activity of pineal NAT, an enzyme involved in the biosynthesis of the putative pineal hormone melatonin. The increase was greater than 60-fold when POB was administered to ganglionectomized rats. NAT induction after POB administration to ganglionectomized rats was not influenced by adrenalectomy, suggesting that the response to POB was not mediated through the release of catecholamines from adrenomedullary catecholamine stores. To determine whether the pharmacologic site of the activity of POB was located within the pineal body itself, pineals were incubated with POB in organ culture. Significant induction of pineal NAT was not observed when pineals were cultured with POB alone. However, POB shifted the dose-response curve for NAT induction by norepinephrine (NE) to the left. Modulation of NAT induction by POB in organ culture was blocked by dl-propranolol HCl, suggesting that such modulation is mediated through a beta adrenergic mechanism. POB did not modulate NE-mediated NAT induction in pineals extracted from superior cervical ganglionectomized rats. Similarly, the modulatory response to POB was eliminated by 24-hr preincubation in culture medium. These results suggest that elements that are disrupted after ganglionectomy or during a period of preincubation are vital for expression of the modulatory activity of POB.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗
PubMed1983

Inhibition by sodium butyrate of enzyme induction by glucocorticoids and dibutyryl cyclic AMP. A role for the rapid form of histone acetylation.

We have found that butyrate selectively inhibits hormonal induction of a few specific proteins and messenger RNAs in hepatoma cells. The fatty acid salt reversibly abolishes induction of tyrosine aminotransferase by dexamethasone and dibutyryl cyclic AMP in HTC cells by inhibiting the production of tyrosine aminotransferase messenger RNA. Half-maximal inhibition of enzyme induction occurred in 0.9 mM butyrate. This effect is highly specific, since 4 h after the addition of butyrate to induced HTC cells, the relative abundance of only five messenger RNA species out of several hundred observable on two-dimensional gels of translational products is changed. Upon removal of the butyrate from cell cultures pretreated with dexamethasone, tyrosine aminotransferase activity begins to increase more rapidly than if dexamethasone is added to control cultures, indicating that part of the induction process occurs in the presence of butyrate. A dose-dependent reduction of fast histone acetylation by butyrate was demonstrated by treating cells with butyrate followed by a short pulse with [3H]acetate and chase in a high concentration of butyrate. The butyrate concentration test range over which rapid histone acetylation is inhibited is similar to that which inhibits enzyme induction to the same extent. In contrast, the slow form of histone acetylation is unaffected in the concentration range examined. The induction of tyrosine aminotransferase by dexamethasone is delayed in hypoacetylated cells. This lag is consistent with the time required to initiate the recovery of the fast form of histone acetylation after its transient disappearance (Covault, J., Perry, M., and Chalkley, R. (1982) J. Biol. Chem. 257, 13433-13440). We conclude that sodium butyrate interferes with the ability of dexamethasone and dibutyryl cyclic AMP to increase production of several specific species of messenger RNA in hepatoma cells. This effect correlates well with its ability to reduce rapid acetylation of histones in HTC cells; we discuss potential roles of rapid histone acetylation in modulating hormonal stimulation of transcription.

Acetylation↗
PubMed1984

Kinetics of beta-glucuronidase induction by androgen. Genetic variation in the first order rate constant.

Measurements of enzyme activity, rates of protein synthesis, and mRNA activity suggest that the induction of beta-glucuronidase in mouse kidney in response to androgen is regulated at a pretranslational level. Following an initial lag period, the rate and extent of induction follow the rules of simple turnover kinetics and can be described in terms of a zero order rate constant for acquisition of mRNA activity (ka) and a first order rate constant for loss of activity (kb). Genetic variation in kb, described here for the first time, alters the half-time and extent of induction. Variation in kb is independent of previously described variation in ka and, unlike changes in ka, is not associated with change in the lag time. The DNA sequences determining kb, like those determining ka, are genetically linked to the structural gene for beta-glucuronidase. Following the removal of androgen, beta-glucuronidase activity, rate of synthesis, and mRNA activity all decline rapidly with half-lives of 1-2 days. Even in the most rapidly inducing strains, this is significantly faster than the half-time for induction determined by kb. Furthermore, genetic variation in kb does not affect the rate of de-induction. These facts suggest that kb may not describe the turnover of beta-glucuronidase mRNA, but rather the turnover of another step in the induction process.

Animals↗
PubMed1994

Transforming growth factor-beta 1, but not dexamethasone, down-regulates nitric-oxide synthase mRNA after its induction by interleukin-1 beta in rat smooth muscle cells.

Nitric oxide (NO), which accounts for the biologic properties of endothelium-derived relaxing factor, is synthesized from L-arginine by nitric-oxide synthase (NOS). Two classes of NOS have been identified: a constitutive, calcium-dependent isozyme (cNOS) and an inducible, calcium-independent isozyme (iNOS). NO is generated after the induction of iNOS by cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha. As a potent vasodilator, NO may have an important role in the severe hypotension of septic shock. We investigated whether dexamethasone and transforming growth factor-beta 1 (TGF-beta 1) suppress iNOS mRNA after its induction by IL-1 beta. We found that IL-1 beta induced iNOS mRNA in rat aortic smooth muscle cells (RASMC) in a dose- and time-dependent fashion. IL-1 beta promoted a dramatic and prolonged induction of RASMC iNOS mRNA that peaked at 48 h. Dexamethasone prevented this induction of iNOS mRNA only when given before the addition of IL-1 beta. In contrast, TGF-beta 1 inhibited the induction of iNOS mRNA and NO production in RASMC both before and after the addition of IL-1 beta. After 24 h of IL-1 beta stimulation, TGF-beta 1 down-regulated the iNOS mRNA that had been induced during this initial time period. In nuclear run-on experiments, we found that the down-regulation of iNOS mRNA by TGF-beta 1 in RASMC occurred at the transcriptional level. Our observation that TGF-beta 1 mediates inhibition of RASMC iNOS mRNA after its induction by cytokines may be an important insight into the treatment of septic shock.

Amino Acid Oxidoreductases↗
PubMed1995

Induction of liver microsomal cytochrome P450 in cynomolgus monkeys.

The aim of this study was to determine whether treatment of cynomolgus monkeys (Macaca fasicularis) with phenobarbital, beta-naphthoflavone, or dexamethasone causes an induction of microsomal crytochrome P450 (CYP) enzymes that are structurally and functionally related to rat enzymes belonging to the CYP1A, CYP2B, and CYP3A gene families. Oral treatment of male and female monkeys with phenobarbital resulted in a marked induction of a protein recognized by antibody against rat CYP2B1, as determined by Western immunoblotting. This protein, presumably a CYP2B enzyme, was not detectable in untreated monkeys, and was modestly inducible by dexamethasone but not beta-naphthoflavone. Induction of this CYP2B enzyme by phenobarbital was associated with a relatively large increase (up to 5-fold) in the rate of testosterone 16 beta-hydroxylation. Antibody, against rat CYP2B1 markedly inhibited this reaction in liver microsomes from phenobarbital-treated monkeys, but not from control monkeys. Consequently, the antibody-inhibitable rate of testosterone 16 beta-hydroxylation increased 17-fold after treatment of monkeys with phenobarbital, which is comparable with the situation in rats. In contrast to the rat CYP2B enzymes, the monkey CYP2B enzyme had little or no capacity to convert testosterone to 16 alpha-hydroxytestosterone or androstenedione, and had negligible capacity to O-dealkylate 7-pentoxyresorufin and 7-benzyloxyresorufin. Oral treatment of male and female monkeys with beta-naphthoflavone resulted in a marked induction of a protein recognized by polyclonal and monoclonal antibodies against rat CYP1A1 or against both CYP1A1 and CYP1A2. This protein was apparently a mixture of CYP1A1 and CYP1A2, neither of which was readily detectable in liver microsomes from control monkeys or monkeys treated with phenobarbital or dexamethasone. Induction of monkey CYP1A1/2 was associated with a marked increase in the O-dealkylation of 7-methoxyresorufin (up to 65-fold), the O-dealkylation of 7-ethoxyresorufin (up to 30-fold), and the N3-demethylation of caffeine (up to 17-fold), but only a 2-fold increase in benzo[a]pyrene 3-hydroxylation. Polyclonal antibodies against CYP1A1 markedly inhibited the N3-demethylation of caffeine and the O-dealkylation of 7-methoxy- and 7-ethoxyresorufin by liver microsomes from beta-naphthoflavone-treated monkeys, and partially inhibited the 3-hydroxylation of benzo[a]pyrene, indicating that monkey CYP1A1 and/or CYP1A2, like the corresponding rat enzymes, can catalyze all four reactions. Treatment of monkeys with phenobarbital resulted in a 2- to 3-fold induction of a protein recognized by antibody against rat CYP3A1. This protein (CYP3A8 or an immunochemically related enzyme) was constitutively expressed in untreated monkeys of both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗
PubMed1993

Role of protein kinase C in tumor necrosis factor induction of endothelial cell urokinase-type plasminogen activator.

Tumor necrosis factor (TNF) can promote endothelial cell transcription, synthesis, and secretion of urokinase plasminogen activator (uPA) augmenting extracellular matrix remodeling and influencing cellular differentiation. In this report, the role of the protein kinase C (PKC) pathway in mediating TNF induction of uPA in human umbilical vein endothelial cells is described. The PKC inhibitors (H-7, staurosporine, and calphostin C), but not HA-1004, inhibited TNF-induced uPA expression, synthesis, and secretion in a dose-dependent manner. Analysis of cell-free conditioned medium obtained from PKC inhibitor-treated cultures by micro-enzyme-linked immunosorbent assay methodologies using uPA- and plasminogen activator inhibitor type 1 (PAI-1)-specific monoclonal antibodies indicate that the decrease in uPA activity observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography was a direct result of decreased extracellular uPA antigen and not a consequence of increased PAI-1 antigen. The effect of PKC inhibitors was specific for TNF-mediated increased uPA expression because cytokine induction of PAI-1 was not influenced by these agents. Northern blot analyses also showed that PKC inhibitor treatment of endothelial cells resulted in a decreased steady-state level of uPA mRNA with no measurable change in PAI-1 mRNA in cultures incubated with TNF. Downregulation of cellular PKC by 18 hours of phorbol myristate acetate (PMA) pretreatment of endothelial cell cultures abolished TNF-mediated extracellular uPA induction. This effect was specific for PMA because 4-alpha PMA pretreatment of cells, which does not stimulate PKC, was ineffective in altering TNF induction of endothelial cell uPA. Induction of PKC directly with PMA, mezerein, and (-)-octylindolactam V increased endothelial cell levels of extracellular uPA in a time- and dose-dependent manner. In addition, this increase in endothelial cell extracellular uPA activity mediated by PKC agonists could be inhibited with PKC inhibitors. Endothelial cells treated with TNF acquire the ability to invade extracellular matrix and reorganize into tube-like structures when grown on Matrigel-coated culture dishes, a behavior blocked by H-7, but not by HA 1004. In summary, these data implicate a role for the PKC pathway in the TNF-mediated induction of uPA expression, subsequent matrix remodeling, and the formation of tube-like structures, a process important in neovascularization, wound healing, and leukocyte extravasation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

The influence of aging on the metabolism of simultaneously administered hexobarbital enantiomers and antipyrine before and after phenobarbital induction in male rats: a longitudinal study.

The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Clm AP), R-HB (Clm R-HB) and S-HB (Clm S-HB) were used as indicators for P450 enzyme activities in vivo. This also included the assessment of the clearances of formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl-->HMA), 4-hydroxyantipyrine (Cl-->OHA) and norantipyrine (Cl-->NORA). Aging appeared to have little influence on the pharmacokinetics of the model compounds. By contrast, the influence of PB pretreatment on Clm AP changed dramatically with aging. The extent of induction decreased from 4.5-fold at 6 months to 1.7-fold at 30 months. Aging influenced the clearances of formation of the three metabolites differentially. Clm S-HB was about six times higher than Clm R-HB without induction. After PB induction, S-HB did not reach detectable levels in plasma at 6, 12 and 24 months. At 30 months, PB pretreatment resulted in a significantly decreased Clm S-HB when compared with the uninduced state. The extent of induction of R-HB metabolism had decreased strongly at 24 and 30 months. The present results clearly indicate that in the aged rat, the P450 enzyme system is much less sensitive to PB induction.

Aging↗
PubMed1994

Regulation of cytochrome P-4501A and cytochrome P-4502E induction in the rat during the production of interferon alpha/beta.

The down regulation of constitutive hepatic microsomal cytochromes P-450 (P450) by interferons has been well described in experimental animals and humans, however the down regulation of induced forms of P450 has not been documented clearly. Differential down regulation of constitutive and induced P450 could alter the proportions of P450 enzymes and, hence, the relative bioactivation/detoxification of xenobiotics. We investigated the effects of polyinosinic acid-polycytidylic acid, a potent stimulator of interferon alpha/beta production on CYP1A and CYP2E induction in the rat. Polyinosinic acid-polycytidylic acid down regulated the constitutive and pyridine-induced expression of CYP2E1 and the pyridine- and beta-naphthoflavone-induced expression of CYP1A1 as demonstrated by metabolic activity and immunoblot analyses. Depression of CYP2E1 and CYP1A1 protein expression by polyinosinic acid-polycytidylic acid was accompanied by a corresponding decrease in mRNA encoding these proteins. Induction of CYP1A2 mRNA also was depressed. Therefore, interferon alpha/beta down regulated induction of members of the CYP1A and CYP2E subfamilies at a pretranslational level independent of the mechanism of induction. Induction of the CYP1A and CYP2E subfamilies did not confer resistance to down regulation by interferon, although the magnitude of down regulation by interferon appeared to be influenced by the magnitude of P450 induction. The potential significance of down regulation of induced P450 in the clearance of certain therapeutic agents and in xenobiotic bioactivation and detoxification is discussed.

Animals↗
PubMed1995

Parallel induction of heme oxygenase-1 and chemoprotective phase 2 enzymes by electrophiles and antioxidants: regulation by upstream antioxidant-responsive elements (ARE).

BACKGROUND: Heme oxygenase (HO; EC 1.14.99.3) catalyzes the conversion of heme to biliverdin, which is reduced enzymatically to bilirubin. Since bilirubin is a potent antioxidant and heme a pro-oxidant, HO may protect cells against oxidative damage. HO-1 is highly inducible by diverse chemical agents, resembling those evoking induction of phase 2 enzymes (i.e., Michael reaction acceptors, heavy metals, trivalent arsenicals, and sulfhydryl reagents). Phase 2 enzymes (glutathione transferases; NAD (P)H:quinone reductase; glucuronosyltransferases) are regulated by antioxidant-responsive elements (ARE), and their induction protects against chemical carcinogenesis. Is HO-1 regulated by chemical agents and enhancer elements similar to those controlling phase 2 enzymes? MATERIALS AND METHODS: Induction of HO-1 by phorbol ester and heavy metals is transcriptionally controlled through a 268-bp SX2 fragment, containing two phorbol ester-responsive (TRE) sites (TGAC/GT C/AA) which overlap ARE consensus sequences (TGACNNNGC). Therefore, mutations of the SX2 element designed to distinguish ARE from TRE were inserted into chloramphenicol acetyltransferase (CAT) reporter plasmids, and the response of the CAT activity of murine hepatoma cells stably transfected with these constructs was examined with a wide range of inducers of phase 2 enzymes. RESULTS: All compounds raised HO-1 mRNA and CAT expression constructs containing wild-type SX2. When the SX2 region was mutated to alter TRE consensus sequences without destroying the ARE consensus, full inducibility was preserved. Conversely, when the ARE consensus was disturbed, inducibility was abolished. CONCLUSION: Induction of heme oxygenase-1 is regulated by several chemically distinct classes of inducers (mostly electrophiles), which also induce phase 2 enzymes, and these inductions are mediated by similar AREs. These findings support the importance of HO-1 as a protector against oxidative damage and suggest that HO-1 induction is part of a more generalized protective cellular response that involves phase 2 enzymes.

Antioxidants↗
PubMed1996

Glucocorticoid receptor-independent transcriptional induction of cytochrome P450 3A1 by metyrapone and its potentiation by glucocorticoid.

Metyrapone administration to 21- and 90-day-old male rats causes a transcriptional induction of the hepatic glucocorticoid-inducible CYP3A1 gene within an hour as determined by nuclear run-on experiments. Analyses performed 24 hr after metyrapone administration in both ages of rat demonstrate that the transcriptional induction of CYP3A1 gene expression is followed by significant increases in CYP3A1 mRNA, CYP3A-immunoreactive microsomal protein and total microsomal cytochrome P450 (CYP). In 21-day-old rats, there is a significant increase in microsomal CYP3A dependent steroid 6 beta-hydroxylase activity but not in 90-day-old rats, possibly because of a slower clearance of this drug, which inhibits CYP activities. In hepatocytes cultured in serum- and glucocorticoid hormone-free medium, metyrapone alone induces CYP3A1 mRNA expression, which demonstrates that metyrapone transcriptionally induces hepatic CYP3A1 by a direct interaction with the liver. Metyrapone does not compete with the binding of the synthetic glucocorticoid and potent transcriptional CYP3A1 inducer dexamethasone to the glucocorticoid receptor (GR) in soluble fractions from liver. This suggests that metyrapone is not a ligand for the GR and induces CYP3A1 by a mechanism independent of the GR. Addition of glucocorticoid to cultured hepatocytes at levels that induce GR-dependent genes potentiate CYP3A1 mRNA induction by metyrapone without inducing CYP3A1 mRNA alone. A GR-dependent mechanism may therefore mediate the potentiation of CYP3A1 transcriptional induction by metyrapone. The CYP3A1 transcriptional inducer and glucocorticoid antagonist pregnenolone 16 alpha-carbonitrile at 100 microM blocks dexamethasone binding to the GR in 21-day-old rat liver soluble fractions but is less effective in 90-day-old rat liver soluble fractions in contrast with 10 microM glucocorticoid antagonist RU486, which is equally effective at blocking dexamethasone binding to the GR. The inability of pregnenolone 16 alpha-carbonitrile to fully compete with dexamethasone for cytosolic binding in adult animals suggests that there may exist variant receptors with different affinities for dexamethasone and pregnenolone 16 alpha-carbonitrile and may explain the mechanism by which low concentrations of dexamethasone potentiate the transcriptional induction of CYP3A1 mediated by high concentrations of pregnenolone 16 alpha-carbonitrile [J. Biol, Chem. 270:28917-28923 (1995)]. Examination of membrane-bound dexamethasone binding activity, with which other steroidal and nonsteroidal CYP3A inducers have been shown to compete, indicates that binding activity is detectable in 90- but not 21-day-old rat liver microsomes. The absence of membrane-bound glucocorticoid binding site activity and the presence of a functional CYP3A1 transcriptional response in 21-day-old rats suggest that membrane-bound glucocorticoid binding site activity is not involved in the transcriptional activation of CYP3A1 expression. These data suggest that both glucocorticoids and nonsteroidal compounds may trigger the transcriptional induction of CYP3A1 by a GR-independent mechanism that may be potentiated by a GR-dependent mechanism.

Aging↗
PubMed1997

Human NAD(P)H:quinone oxidoreductase induction in human hepatoma cells after exposure to industrial acrylates, phenolics, and metals.

Induction of the endogenous human NAD(P)H:quinone oxidoreductase (HQOR1) gene in the human hepatoma cell line HepG2 was measured at both the enzyme activity and RNA levels after exposure to a variety of industrial compounds. An RNA probe was designed that was complementary to portions of both the coding region and the 3'-nontranslated region unique to the largest (2.7-kilobase) HQOR1 transcript. Induction by three strong inducers of HQOR1 verified the utility of the antisense RNA probe. Ten industrial chemicals were evaluated as potential inducers, i.e. acrylonitrile, Sb2O3, BaO, CdCl2, CuCl, ethyl acrylate, methyl acrylate, MoO3, phenol, and toluene. Induction at the RNA level was about 2-fold higher than at the enzyme activity level except in the case of acrylonitrile, for which induction at the enzyme activity and RNA levels was similar. There was no preferential induction of the 2.7-kilobase transcript for any chemical tested, including 2,3,7,8-tetrachloro-dibenzo-p-dioxin, which had previously been reported to preferentially induce this transcript. Six of the 10 industrial chemicals, including four previously untested chemicals (phenol, Sb2O3, CuCl, and MoO3), were found to induce the HQOR1 gene. By comparison, previous studies in rodent systems failed to accurately predict the human HQOR1 gene response. Two chemicals previously shown to be inducers in rodent systems (methyl acrylate and CdCl2 failed to induce the HQOR1 gene. These results emphasize the importance of analyzing induction of the endogenous human gene, rather than simply extrapolating from rodent systems or gene fusion experiments.

Acrylonitrile↗
PubMed2006

Rate of pathologic complete responses to docetaxel, cisplatin, and fluorouracil induction chemotherapy in patients with squamous cell carcinoma of the head and neck.

OBJECTIVE: To report the rate of pathological complete response after induction chemotherapy with the docetaxel, cisplatin, and fluorouracil (TPF) combination. DESIGN: Retrospective cohort analysis. SETTING: Tertiary care academic cancer center, between June 1999 and May 2004. PATIENTS: Seventy-two patients with newly diagnosed squamous cell carcinoma of the head and neck; 68 (95%) of the patients had stage IV, locally advanced disease. INTERVENTIONS: Three cycles of induction chemotherapy followed by a biopsy of the primary site. All patients subsequently underwent chemotherapy with 3 cycles of TPF. MAIN OUTCOME MEASURE: Rate of pathological complete response at the primary site after induction chemotherapy with 3 cycles of TPF. RESULTS: Biopsy results were negative for cancer in 64 patients (89%) and positive in 8 patients (11%). The median follow-up was 2 years. In the positive biopsy result group, 2 (25%) of 8 patients died of disease vs 3 (4%) of 64 patients in the negative biopsy result group. Twenty-nine neck dissections were performed; results were positive in 7 patients (all alive with no evidence of disease) and negative in 22 patients (21 alive with no evidence of disease). The overall 2- and 5-year progression-free survival is currently projected at 85% and 85%, respectively; the overall 2- and 5-year survival, at 95% and 90%, respectively. Importantly, T4 presentation did not predict a positive biopsy result at the primary site or a positive neck dissection result (P = .60 and P = .56, respectively). N3 presentation (12 patients) did not predict a positive biopsy result at the primary site (P = .87) but did correlate with positive neck dissection results in 6 of 12 patients (P<.001). CONCLUSIONS: Induction chemotherapy with the TPF regimen results in a high pathological complete response rate (89%). This rate is higher than with the cisplatin plus fluorouracil combination therapy, which was reported to be between 25% and 50% in previous studies. Chemoradiotherapy is currently an accepted standard of care, but induction chemotherapy continues to be investigated. Based on recent phase 3 trial results and the data presented herein, we propose that the 3-drug combination be used as the new platform when administering induction chemotherapy.

Adult↗
PubMed2000

Development of a LAC4 promoter-based gratuitous induction system in Kluyveromyces lactis.

A gratuitous induction system based on the strong, indigenous LAC4 promoter was developed for Kluyveromyces lactis. To prevent consumption of the inducer galactose, a strain with a gal1-209 mutation was employed; this mutation disables the galactokinase function but retains the regulatory function for induction. The Escherichia coli lacZ gene (encoding beta-galactosidase) is functional in K. lactis and was used as the reporter gene downstream of the LAC4 promoter on a multicopy plasmid. The gal1-209 strain exhibited several unexpected phenomena, including partial consumption of the inducer galactose (although at a much slower rate relative to GAL1 strains) and growth inhibition at high concentrations of galactose. These unusual characteristics, however, did not prevent the successful construction of a strong gratuitous induction system. Due to the low rate of inducer consumption for the gratuitous strain, very low concentrations of galactose (1:20 galactose:glucose) resulted in high-level induction. Under these conditions, beta-galactosidase specific and volumetric activities were 4.2- and 5.5-fold higher, respectively, than those for the "GAL1" nongratuitous strain. This research demonstrated the improved productivity possible via LAC4 promoter-based gratuitous induction (and thus a more stable inducer concentration). The effects of various carbon source concentrations on growth and induction were also determined.

Cell Division↗
PubMed1996

Effect of antioxidants on lipopolysaccharide-stimulated induction of mangano superoxide dismutase mRNA in bovine pulmonary artery endothelial cells.

Generation of reactive oxygen species (ROS) is a common event in the pathogenesis of acute lung injury. Endothelial cells may be both a target and a source of the ROS. Exposure of bovine pulmonary endothelial cells (BPAEC) to lipopolysaccharide (LPS) has been shown to result in intracellular generation of both ROS and the antioxidant enzyme, mangano superoxide dismutase (MnSOD). The present study investigates whether alterations in intracellular oxidant state affect LPS-stimulated cytotoxicity and induction of MnSOD mRNA. BPAEC were pretreated with either the free radical scavenger, dimethylsulfoxide (DMSO), the xanthine oxidase inhibitor, allopurinol, or N-acetylcysteine (a cysteine derivate capable of increasing glutathione stores) prior to exposure to LPS (0.1 microgram/ml) for either 4, 8 or 18 hours. We found that pretreatment of BPAEC with DMSO blocked both LPS-induced cytotoxicity and induction of the MnSOD gene. Nuclear run-off experiments demonstrated that LPS-stimulated induction of the MnSOD mRNA occurred at the transcriptional level and that DMSO blocked this event. Pretreatment with allopurinol also prevented the cytotoxicity associated with LPS but, in contrast to DMSO, did not alter induction of MnSOD mRNA. N-acetylcysteine did not affect the LPS-stimulated cytotoxicity but resulted in an early and transient reduction in induction of the MnSOD gene. We conclude that LPS stimulates generation of intracellular ROS that regulate induction of the MnSOD gene at the transcriptional level further, we conclude that LPS-stimulated cytotoxicity involves both the xanthine oxidase pathway and perhaps intracellular generation of hydroxyl radicals. The difference in the protective effect between DMSO, NAC and allopurinol suggest that upregulation of the MnSOD gene does not contribute to LPS-induced cytotoxicity.

Acetylcysteine↗