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PubMed1993

Relationship between hydrocarbon structure and induction of P450: effects on protein levels and enzyme activities.

1. Treatment of male rat with the small aromatic hydrocarbons, benzene, toluene, ethylbenzene, n-propylbenzene, m-xylene, and p-xylene increased several P450-dependent activities, with ethylbenzene, m-xylene, and n-propylbenzene producing the greatest response. Hydrocarbon treatment differentially affected toluene metabolism, producing a response dependent on the metabolite monitored. In untreated rats, benzyl alcohol was the major hydroxylation product of toluene metabolism, comprising > 99% of the total metabolites formed. Hydrocarbon treatment increased the overall rate of toluene metabolism by dramatically increasing the amount of aromatic hydroxylation. Ethylbenzene, n-propylbenzene and m-xylene were the most effective inducers of aromatic hydroxylation of toluene. In contrast, production of the major toluene metabolite benzyl alcohol was increased only after treatment with m-xylene. 2. P450 2B1/2B2 levels were induced by each of the hydrocarbons examined, with the magnitude of induction increasing with increasing hydrocarbon size. P450 1A1 was also induced after hydrocarbon exposure; however, the degree of induction was smaller than that observed for P450 2B1/2B2. P450 2C11 levels were suppressed after treatment with benzene, ethylbenzene and n-propylbenzene. 3. Taken together these results display two induction patterns. The first generally corresponds to changes in the P450 2B subfamily, where activities (e.g. the aromatic hydroxylations of toluene) were most effectively induced by ethylbenzene, n-propylbenzene and m-xylene. In the second, induction was observed only after m-xylene treatment, a pattern that was found when the metabolism of the substrate was catalysed by both the P450 2B subfamily and P450 2C11. Hydrocarbons that both induced P450 2B1/2B2 and suppressed P450 2C11 (such as ethylbenzene and n-propylbenzene) showed little change in activities catalysed by both isozymes (e.g. aliphatic hydroxylation of toluene, and aniline hydroxylation); however, m-xylene treatment led to elevated P450 2B1/2B2 levels without significantly suppressing P450 2C11. m-Xylene produced significant increases in activities efficiently catalysed by both isozymes. Therefore, the unique induction pattern observed after m-xylene treatment can be accounted for by induction of P450 2B1/2B2 without concomitant suppression of P450 2C11.

Animals↗
PubMed1994

Coordinate induction of hepatic fatty acyl-CoA oxidase and P4504A1 in rat after activation of the peroxisome proliferator-activated receptor (PPAR) by sulphur-substituted fatty acid analogues.

1. In the liver of rat fed a single dose of 3-thia fatty acids, 3-dithiahexadecanedioic acid (3-thiadicarboxylic acid) and tetradecylthioacetic acid, steady-state levels of P4504A1 and fatty acyl-CoA oxidase mRNAs increased in parallel. The increases were significant 8 h after administration, reaching a maximum after 12 h and decreased from 12 to 24 h after administration. 2. The corresponding enzyme activities of P4504A1 and fatty acyl-CoA oxidase were also induced in a parallel manner by the 3-thia fatty acids. The enzyme activities were significantly increased 12 h after administration and increased further after 24 h. This may reflect a possible effect of the 3-thia fatty acids not only on mRNA levels, but also on the translation and degradation rate of the two enzymes. 3. Repeated administration of 3-thia fatty acids resulted in an increase of the specific P4504A1 protein accompanied with an increased lauric acid hydroxylase activity. The correlation between induction of P4504A1 and fatty acyl-CoA oxidase mRNAs and their enzyme activities may reflect a coordinated rather than a causative induction mechanism, and that these genes respond to a common signal. This suggests that the increased P450 activity may not be responsible or be a prerequisite for fatty acyl-CoA oxidase induction. 4. Since the peroxisome proliferator-activated receptor (PPAR) plays a role in mediating the induction of fatty acyl-CoA oxidase, we analysed the activation of PPAR by fatty acids and sulphur-substituted analogues utilizing a chimera between the N-terminal and DNA-binding domain of the glucocorticoid receptor and the putative ligand-binding domain of PPAR. Arachidonic acid activated this chimeric receptor in Chinese hamster ovary cells. Inhibitors of P450 did not affect the activation of PPAR by arachidonic acid. Furthermore, dicarboxylic acids including 1,12-dodecanedioic acid or 1,16-hexadecanedioic acid only weakly activated the chimera. 3-Thidicarboxylic acid, however, was a much more effective activator than the non-sulphur-substituted analogues. In conclusion, the data suggest that the most likely mechanism of the induction process is fatty acid-induced activation of PPAR, which then leads to a coordinated induction of P4504A1 and fatty acyl-CoA oxidase.

Acyl-CoA Oxidase↗
PubMed1989

Influence of hypothyroidism on the ontogenic development of tyrosine hydroxylase induction in the adrenal glands of the rat.

The ontogenic development of the transsynaptic induction of adrenal tyrosine hydroxylase (TH), evoked by reserpine and nicotine was studied in control and hypothyroid young rats, aged 3-52 days. The enzymatic induction was measured as an increase in the enzyme activity, since this increase was shown to be impaired either by an inhibitor of RNA synthesis or by a ganglionic blocker. In the control animals, TH induction elicited by reserpine increases between 3 and 32 days of age. In the hypothyroid rats, the enzymatic induction is impaired up to 32 days; at 52 days the induction is similar in both groups of animals. When nicotine is used as a stimulating agent, hypothyroidism still impairs the enzymatic induction at 5 and 21 days, indicating that at least one of the mechanisms inhibited by hypothyroidism is localized in the adrenal chromaffin cells. The present results, taken together with previous findings dealing with adrenal epinephrine secretion, show that the thyroid hormones play a crucial role in the responses of the adrenal medulla to a stimulation in the developing rat, while they have no effect in the adult.

Adrenal Glands↗
PubMed2000

Protein kinase C epsilon is required for the induction of mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages.

LPS induces in bone marrow macrophages the transient expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). Because MKP-1 plays a crucial role in the attenuation of different MAPK cascades, we were interested in the characterization of the signaling mechanisms involved in the control of MKP-1 expression in LPS-stimulated macrophages. The induction of MKP-1 was blocked by genistein, a tyrosine kinase inhibitor, and by two different protein kinase C (PKC) inhibitors (GF109203X and calphostin C). We had previously shown that bone marrow macrophages express the isoforms PKC beta I, epsilon, and zeta. Of all these, only PKC beta I and epsilon are inhibited by GF109203X. The following arguments suggest that PKC epsilon is required selectively for the induction of MKP-1 by LPS. First, in macrophages exposed to prolonged treatment with PMA, MKP-1 induction by LPS correlates with the levels of expression of PKC epsilon but not with that of PKC beta I. Second, Gö6976, an inhibitor selective for conventional PKCs, including PKC beta I, does not alter MKP-1 induction by LPS. Last, antisense oligonucleotides that block the expression of PKC epsilon, but not those selective for PKC beta I or PKC zeta, inhibit MKP-1 induction and lead to an increase of extracellular-signal regulated kinase activity during the macrophage response to LPS. Finally, in macrophages stimulated with LPS we observed significant activation of PKC epsilon. In conclusion, our results demonstrate an important role for PKC epsilon in the induction of MKP-1 and the subsequent negative control of MAPK activity in macrophages.

Bone Marrow Cells↗
PubMed2005

In vitro and in vivo induction of heme oxygenase 1 in mouse macrophages following melanocortin receptor activation.

RAW264.7 cell incubation with adrenocorticotrophin (ACTH) led to a time-dependent (4-24 h) and concentration-related (1-100 ng/ml) induction of heme oxygenase (HO)-1, and this was a specific effect, because the pattern of expression of other cellular proteins (HO-2, heat shock proteins 70 and 90) was not modified by ACTH. Combined RT-PCR and Western blot analyses revealed expression of the melanocortin receptor (MC-R) types 1 and 3, but not 4, in these cells. However, use of more selective agonists (including melanotan (MTII)) indicated a predominant role for MC3-R in the induction of HO-1 expression and activity. Relevantly, ACTH and MTII incubation with primary peritoneal macrophages (Mphi) also induced HO-1 expression. The potential link between MC3-R dependent cAMP formation and HO-1 induction was ascertained by the following: 1) ACTH and MTII produced a concentration-dependent accumulation of cAMP in RAW264.7 cells, and 2) whereas a selective inhibitor of cAMP-dependent protein kinase A abrogated ACTH- and MTII-induced HO-1 expression, a soluble cAMP derivative promoted HO-1 induction both in RAW264.7 cells and primary Mphi. HO-1 induction in peritoneal Mphi was also detected following in vivo administration of MTII, and appeared to be functionally related to the antimigratory effect of this melanocortin, as determined with a specific inhibitor (zinc protoporphyrin IX). In conclusion, this study highlights a biochemical link between MC-R activation and HO-1 induction in the Mphi, and proposes that this may be of functional relevance in determining MC-R-dependent control of the host inflammatory response.

Amino Acid Sequence↗
PubMed1999

Induction of CYP1A2 by phenobarbital in the livers of aryl hydrocarbon-responsive and -nonresponsive mice.

The effects of phenobarbital treatment on the expression of the cytochrome P-450 (CYP or P-450) enzyme CYP1A2 in the livers of mice of various strains were examined. Phenobarbital induced the expression of CYP1A2 at the levels of mRNA, protein, and enzyme activity (methoxyresorufin O-demethylation and metabolic activation of 2-amino-3-methylimidazo[4,5-f]quinoline) in both aryl hydrocarbon-responsive [C57BL/6NCrj (C57BL/6), C3H/HeJSlc] and -nonresponsive (DBA/2NCrj, AKR/JSea, NZB/NSlc) mouse strains. The induction of CYP2B10, which is known as a phenobarbital-inducible P-450 in mice, was prominent in the livers of all five strains examined, whereas clear inductive effects on the P-450 CYP2B9 were not observed in female C57BL/6 and female DBA/2NCrj mice. These results indicate that CYP1A2 is a member of the family of phenobarbital-inducible genes in mice and suggest that the aryl hydrocarbon receptor-dependent induction pathway is not involved in the induction of CYP1A2. This concept is in accordance with those proposed by other laboratories recently using the AhR knockout mice. The following are new observations of this report. The magnitude of the increases in the CYP1A2 mRNA, protein, and enzyme activities were comparable among these three levels (ranging from 1.4- to 3. 1-fold), suggesting that the induction of CYP1A2 by phenobarbital is mainly determined at a pretranslational level. Cyclobarbital, pentobarbital, and secobarbital also induced CYP1A2 mRNA in primary culture hepatocytes from C57BL/6 mice. Barbital, in contrast, did not show any clear inductive effect on CYP1A2 mRNA.

Animals↗
PubMed1999

Influence of extracellular matrix overlay and medium formulation on the induction of cytochrome P-450 2B enzymes in primary cultures of rat hepatocytes.

The effect of medium formulation, composition of extracellular matrix overlay, and culture dish material on liver microsomal cytochrome P-450 (CYP) 2B induction by phenobarbital (PB) was investigated in primary cultures of rat hepatocytes. When hepatocytes were maintained on Permanox dishes with an overlay of either collagen (type I) or Matrigel, Williams' E medium was superior to other medium formulations in terms of the magnitude of induction of CYP2B on a per milligram microsomal protein basis. Modified Chee's medium (MCM) and hepatocyte culture medium were intermediate in their capacity to sustain induction of CYP2B by PB, and Dulbecco's modified Eagle's medium was slightly less effective. The overall induction of CYP2B activity by PB was, on average, 50% lower in hepatocytes cultured on polystyrene dishes (LUX). Little or no difference was observed between hepatocytes overlaid with collagen and those overlaid with Matrigel. MCM was superior to Williams' E medium in terms of the yield of microsomal protein and the ultrastructural features of the hepatocyte monolayers. CYP2B induction by PB was optimal after 3 days of treatment in either medium. CYP1A, CYP3A, and CYP4A activities could be induced in vitro by prototypical inducing agents in hepatocytes cultured on Permanox dishes with MCM and a Matrigel overlay to comparable levels observed in vivo. The results of these studies show that medium formulation and culture vessel material, but not the type of extracellular matrix overlay, have significant effects on the induction of CYP enzymes in cultured rat hepatocytes maintained in a sandwich configuration.

Animals↗
PubMed2000

[Ovulation induction therapy and malignant ovarian cancer].

In the authors' institute 1097 patients received treatment for ovarian cancer between the 1st of January, 1960 and the 31st of December, 1997. 92 of them had malignant granulosa cell tumor. In this study the link between ovulation induction therapy and ovarian cancer was analyzed with retrospective questionnaire. 236 questionnaires were shared out among patients with malignant ovarian tumor, who were treated between 1990 and 1997. 7 of 113 patients, who gave correct answers to the questions (6.2%) received ovulation induction therapy. Epithelial ovarian cancer developed in 2 of the cases during, and in 5 cases just 6-16 years after the clomiphene-citrate treatment. None of the 45 patients with granulosa cell tumors received induction therapy. The number of patients admitted because of malignant ovarian tumor before and after the induction therapy was also compared. There was no significant increase in the occurrence of the malignancy. Since 1986 in the in vitro fertilization program of the clinic nearly 1,500 patients were treated with effected ovulation induction drugs causing superovulation. The authors don't know of any development of malignant ovarian tumor, and 732 woman have confirmed this fact. The number of patients deceased in consequence of ovarian cancer in different age groups, and the distribution of the women population in every age group in Hungary, from the year of 1979 was also analyzed. There was no significant increase found in the number of deceased among the studied age groups, moreover a significant decrease among them could be observed. The link between ovulation induction therapy and ovarian cancer can neither be strengthen, nor deny by the result of the study, however the close relationship which seemed to be logical can be queried. To give an exact answer for the question a vast, long-term, prospective of retrospective follow-up case-control study is needed.

Adult↗
PubMed2001

Polycyclic aromatic hydrocarbon/metal mixtures: effect on PAH induction of CYP1A1 in human HEPG2 cells.

Environmental polycyclic aromatic hydrocarbons (PAHs) and metals coexist, and such mixtures could affect the carcinogenicity of PAHs, possibly by modification of PAH induction of the PAH-bioactivating CYP1A. The effect on PAH-mediated CYP1A induction of arsenic, lead, mercury, or cadmium (ranked as the most hazardous environmental metals by the Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry) has thus been investigated. Induction of CYP1A1 by benzo[a]pyrene (BAP), benzo[b]fluoranthene (BBF), dibenzo[a,h]anthracene (DBAHA), benzo[a]anthracene (BAA), or benzo[k]fluoranthene (BKF) was probed by ethoxyresorufin-O-deethylase activity (EROD) in 96-well plates of human HepG2 cells, by immunoblot analysis, and by reverse transcription-polymerase chain reaction. Cells rapidly took up PAHs (BAP, BKF) from medium; by 24 h only 14% remained in the medium, and no detectable PAH bound to well walls. Induction efficiency (relative to dimethyl sulfoxide controls) was in the order BKF (16-fold) > DBAHA (14-fold) > BAA (4-fold) > BAP (3-fold) > BBF (1-fold), all at 5 microM PAH. The metals did not markedly affect cell viability at concentrations of arsenic, 5 microM; lead, 50 microM; mercury, 5 microM; and cadmium, 5 microM. At 5 microM PAH concentration, all of the metals decreased levels of PAH-induced CYP1A1 activities (direct inhibition of EROD activity was excluded) by variable extents and in a PAH-dependent manner. With BAP as inducer decreases in induction were arsenic, 57%; cadmium, 82%; mercury, 4%; and lead, 20%. The decreases were not a consequence of transcriptional down-regulation. One possible conclusion is that these metals could diminish PAH carcinogenic potential by decreasing PAH-mediated induction of their bioactivation by CYP1A1.

Base Sequence↗
PubMed2001

[Induction and kinetic characterization of nitric oxide synthase in hepatocytes].

OBJECTIVE: To study the synergistic responses of nitric oxide synthase (NOS) induction in rat hepatocytes to LPS and various cytokines in vitro and the kinetic characteristics of iNOS. METHODS: The hepatocytes were isolated by in-situ pre-perfusion and collagenase circulatory perfusion of rat livers. The effects of LPS associated with IFN-r, TNF-alpha and IL-1beta or IL-6 on NOS activity, cGMP, and NO(2)(-)+NO(3)(-) were observed in hepatocytes, respectively. Also the kinetic characteristics of this enzyme and dose response of corticosteroids on the induction of iNOS were analyzed. RESULTS: The maximum induction of NOS activity was observed in hepatocytes treated by LPS in combination with IFN-r, TNF-alpha and IL-1beta or IL-6. The kinetic analysis of this iNOS demonstrated specific constants of Km=10.8 micromol/L, Vmax=263.2 pmol/min/mg protein(for L-Arg), and Ki of 0.56, 0.94 micromol/L for competitive inhibitor, L-NMMA and NNA, respectively. The time course of induction showed that iNOS activity peaked at 9 h; however, significant increase in release of NO(2)(-)+NO(3)(-) and cGMP sustained for at least 18 h. Dexamethasone and hydrocortisone dramatically inhibited the NOS induction in hepatocytes in vitro with IC50 of 3.5+/-10(-8)mol/L and 2.6+/-10(-6)mol/L, respectively. CONCLUSIONS: The expression of inductive NOS in hepatocytes requires specific synergetic action of cytokines, and the inducible characteristics may play an important pathogenesis in endotoxemia and septic shock.

Animals↗
PubMed2003

Polycystic ovary syndrome and ovulation induction.

Polycystic ovary syndrome (PCOS) is likely the most common cause of anovulatory infertility. Although many options are available for ovulation induction in these patients, there is currently no evidence-based algorithm to guide the initial and subsequent choices of ovulation induction methods. In obese women with PCOS, mild to moderate weight loss results in improvement of ovulatory dysfunction, and should be advocated at the onset of the evaluation. Clomiphene citrate is currently the 1st line medical therapy for ovulation induction. Glucocorticoids do not result in consistent ovulation and have significant side effects. Exogenous pulsatile GnRH treatment has low ovulation and pregnancy rates with a high risk of miscarriage. The most commonly used medical agents for ovulation induction in clomiphene-resistant women with PCOS are parenteral gonadotropins. Various gonadotropin preparations and different protocols are available; however the risk of multiple pregnancy and ovarian hyperstimulation is high with gonadotropin therapy. The frequent association between PCOS and insulin resistance has prompted recent studies on the effect of insulin-sensitizing agents on spontaneous and as an adjuvant to conventional ovulation induction therapies. Overall, the improvement in ovulation with insulin sensitizing drugs is modest, and unresolved issues such as variability in ovarian response remain to be addressed in future studies. Nevertheless, these agents may be beneficial in a subset of PCOS patients. Surgical ovulation induction methods such as ovarian diathermy have been reported to be moderately effective. However, due to the inherent associated risks and unknown effect on long-term reproductive potential, this modality should be reserved for patients who are clomiphene-resistant and unable or unwilling to proceed to gonadotropin therapy.

Female↗
PubMed2003

The antiangiogenic agent SU5416 down-regulates phorbol ester-mediated induction of cyclooxygenase 2 expression by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity.

Increased expression of cyclooxygenase (COX) 2 and the production of PGs appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness and the stimulation of angiogenesis. The purpose of this study was to determine whether an angiogenic antagonist, SU5416, could inhibit endogenous and phorbol 12-myristate 13-acetate (PMA)-mediated induction of COX-2 expression. SU5416 (5 micro M) inhibited endogenous as well as PMA-mediated induction of COX-2 expression when analyzed by immunoblot and Northern blot analysis. However, COX-1 expression remained unchanged under similar conditions. PMA is a potent inducer of reactive oxygen species that can play an important role during the induction of COX-2 expression. Our results demonstrated that PMA-mediated induction of COX-2 expression was found to be dependent on NADPH oxidase activity. An inhibitor of NADPH oxidase (diphenyleneiodonium chloride) blocked the PMA-mediated induction of COX-2 expression. The oxidase complex exhibited a temporal pattern of activation after exposure to PMA in which maximum activation was observed at 30 min after the addition of PMA. Activation of NADPH oxidase was also inhibited by SU5416, whereas an inhibitor of epidermal growth factor receptor signaling was unable to prevent the PMA-mediated induction of NADPH oxidase activity. When we blocked the PMA-mediated production of reactive oxygen species by blocking NADPH oxidase with SU5416, COX-2 expression and PGE(2) synthesis were also inhibited. Our results suggest that inhibition of NADPH oxidase activity, blocking of COX-2 expression, and PGE(2) synthesis may represent novel targets for SU5416.

Angiogenesis Inhibitors↗
PubMed1991

Studies on the induction of cinnamic acid 4-hydroxylase in potato tuber.

The change in activity of cinnamic acid 4-hydroxylase (CA4H) in potato parenchyma tissue exposed to various conditions has been examined. Maximum induction of CA4H activity was obtained at 18 hr of incubation. Though CA4H induction can occur in dark, over 100% increase in enzyme activity was obtained on exposure of the tissue to light. Actinomycin D and cycloheximide inhibited the induction process. Mn2+, though known to cause an induction of CA4H in Jerusalem Artichoke, strongly inhibited potato CA4H induction. Dithiothreitol enhanced the CA4H activity due to either activation or protection of the enzyme. CA4H induction was significantly regulated at very low concentrations of trans-cinnamate and paracoumarate.

Cycloheximide↗
PubMed1990

Acute and chronic ultraviolet radiation induction of epidermal ornithine decarboxylase activity in hairless mice.

The effects of acute, multiple, and chronic exposure of hairless mice to ultraviolet radiation (UVR) on induction of epidermal ornithine decarboxylase (ODC) (EC 4.1.1.17) activity were investigated. Acute UVR exposure results in a biphasic time course of induction of epidermal ODC activity. Enzyme activity maxima occur at 3 and 24 h postirradiation. The biphasic time course is observed in two different strains of hairless mice (Skh:HR-1 and Jackson HRS/J) when the UVR source is either UBV fluorescent tubes or a solar simulator. The ratio of 24-h/3-h postirradiation ODC activity increases with increasing UVR dose. UVR induction of ODC activity was not significant below the mouse minimum erythemal dose (MED). The 3- and 24-h ODC activities have similar apparent Kms for ornithine (34 and 50 microM, respectively), and thermal stabilities at 52 degrees C (t1/2 = 23 and 18 min, respectively), and exhibit similar half-lives in vivo (t1/2 = 15 and 18 min, respectively). Multiple UVR exposure experiments showed 24-h ODC activity is sensitive to the preexposure history of the mouse, while 3-h ODC is not. Preexposure of hairless mice to several sub-MED levels of simulated solar radiation (SSR) specifically suppresses induction of 24-h ODC by a follow-up 2 x MED of SSR. Preexposure to a single 2 x MED of SSR specifically enhances induction of 24-h ODC induced by a second 2 x MED of SSR administered 48 h after the first. The 3-h ODC was not significantly affected by either preexposure regimen. Preexposure to a single high or low dose of UVA radiation did not affect epidermal ODC activity nor had an effect on ODC induction by UVB radiation. Several weeks of chronic exposure to UVB radiation elevated basal levels of epidermal ODC substantially (up to 350-fold). In these chronically irradiated mice, exposure to 2 x MED SSR resulted in a further 3.5-fold increase in ODC activity over the elevated basal level. These data reveal novel properties of epidermal cell expression of ODC activity in response to acute and chronic UVR insult. The results provide additional insight into the use of ODC as a marker for skin photodamage.

Animals↗
PubMed1990

Induction of superoxide dismutase in leukocytes by paraquat: correlation with age and possible predictor of longevity.

Reactive oxygen species (ROS) are thought to play a role in the aging process as well as in a number of human diseases states. Superoxide dismutase (SOD), an enzyme that scavenges the superoxide anion (O2-) is constitutively expressed in leukocytes and other tissues. When assayed in peripheral blood leukocytes (PBL), constitutive SOD activity shows little variation among individuals of different ages. We have found that significant induction of SOD activity occurs in PBL incubated in vitro with paraquat, an agent known to cause intracellular O2- production. This induction was found to be highly age dependent; lymphocytes from 36 healthy subjects aged 20 to 40 years showed an increase of 85% +/- 10%, versus an increase of only 8% +/- 1% for lymphocytes from 30 healthy subjects aged 65 to 79 years (P less than 10(-4)). Forty subjects, aged 67 to 73 years, who were healthy at the time of assay of leukocyte SOD induction were followed up 5 years later. Nineteen of these subjects had died; all 19 had shown SOD induction of less than 10% (range, 0% to 7%; mean, 2.4%). In contrast, of the 21 survivors (range, 2.5% to 50%; mean, 21%), 12 had shown SOD induction greater than 10%, and 7 had shown SOD induction greater than or equal to 35% (P less than 10(-3)). Thirteen of the 19 deaths were attributable to malignancy or cerebrocardiovascular disease. Preservation of leukocyte SOD inducibility appears to correlate with longevity in elderly individuals and may be of value in predicting resistance to malignancy or fetal cardiovascular events.

Adult↗
PubMed1989

Potentiation of 3-methylcholanthrene induction of rat hepatic cytochrome P450IA1 by dexamethasone in vivo.

The potentiation of the expression of polycyclic aromatic hydrocarbon-inducible cytochromes P450IA1 and P450IA2, and phenobarbital-inducible cytochrome P450IIB1 and NADPH-cytochrome P-450 reductase by dexamethasone in vivo was investigated using adrenalectomized and sham-operated rats. Hepatic cytochrome P450IA1 activity (determined by ethoxyresorufin O-deethylase activity) was induced maximally (30-fold) in both sham-operated and adrenalectomized rats 24 hr after a single injection of 3-methylcholanthrene (10 mg/kg). Dexamethasone (10 mg/kg) increased hepatic tyrosine aminotransferase activity 3- to 4-fold, but had little or no effect on ethoxyresorufin O-deethylase activity. However, dexamethasone potentiated the 3-methylcholanthrene-dependent induction of hepatic P450IA1 activity 2- to 3-fold in adrenalectomized rats and 1.5- to 2-fold in sham-operated rats when administered concomitantly with 3-methylcholanthrene (P less than .05). The dose of dexamethasone required to potentiate 3-methylcholanthrene induction of P450IA1 activity (greater than 1 mg/kg) correlated well with the dose required to induce hepatic tyrosine aminotransferase activity; a marker of glucocorticoid action. Potentiation of 3-methylcholanthrene induction of P450IA1 activity in the rat appears to be tissue specific in that dexamethasone was found not to potentiate 3-methylcholanthrene induction of P450IA1 activity of rat lung or kidney. Cytochrome P450IA1 content induced by 3-methylcholanthrene in the liver was also potentiated 2- to 3-fold by dexamethasone. In contrast, potentiation of 3-methylcholanthrene induction of cytochrome P450IA2 content was not observed. Western blot analyses indicate that the increase in monooxygenase activity induced by 3-methylcholanthrene or 3-methylcholanthrene plus dexamethasone corresponds well only with the induction of cytochrome P450IA1 protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1985

Influence of sedatives on stress-induced trans-synaptic induction of tyrosine hydroxylase.

Rats were exposed to combined enforced swimming and cold stress in order to investigate the influence of the sedative compounds 2-(2-oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1,1-dioxide (supidimide), phenobarbital, and diazepam on stress-induced changes in cyclic adenosine 3',5'-phosphate (cAMP) and trans-synaptic induction of tyrosine hydroxylase (TH) in adrenal glands. Pretreatment with supidimide at greater than or equal to 150 mg/kg suppresses the early poststress rise in cAMP and the delayed TH induction. Phenobarbital at 75 mg/kg slightly inhibits the cAMP increase, but does not significantly interfere with TH induction. Diazepam already at 5 mg/kg completely blocks the stress-induced increase of cAMP, but leaves the TH induction unchanged at dosages up to 20 mg/kg. It is concluded that the stress-induced rise in adrenal cAMP and the trans-synaptic induction of TH are rather coincidental than causally related. Suppression of TH induction by supidimide appears to be a peculiarity of this compound not strictly related to its sedative potency.

Adrenal Glands↗
PubMed1986

Induction of digitoxigenin monodigitoxoside UDP-glucuronosyltransferase activity by glucocorticoids and other inducers of cytochrome P-450p in primary monolayer cultures of adult rat hepatocytes and in human liver.

We have recently proposed that glucocorticoids induce cytochrome P-450p, a liver microsomal hemoprotein originally isolated from rats treated with the antiglucocorticoid pregnenolone 16 alpha-carbonitrile (PCN), through a mechanism that involves a stereospecific recognition system clearly distinguishable from the classic glucocorticoid receptor (Schuetz, E. G., Wrighton, S. A., Barwick, J. L., and Guzelian, P. S. (1984) J. Biol. Chem. 259, 1999-2012). We now report that digitoxigenin monodigitoxoside UDP-glucuronosyltransferase (DIG UDP-glucuronosyltransferase), a liver microsomal enzyme activity induced by PCN in rats, is also inducible, as is P-450p, in primary monolayer cultures of adult rat hepatocytes. DIG UDP-glucuronosyltransferase activity closely resembled reported characteristics of induction of P-450p in its time course of induction, concentration-response relationships, exclusivity of induction by steroids with glucocorticoid properties, unusual rank order of potency of glucocorticoid agonists, unusually high ED50 for induction by glucocorticoids, enhanced induction rather than inhibition by anti-glucocorticoids in the presence of glucocorticoids, and finally, induction by nonsteroidal inducers of P-450p. DIG UDP-glucuronosyltransferase activity was also readily detected in human liver microsomes and was elevated in two patients who had received inducers of P-450p. We conclude that the liver enzymes controlled by the postulated PCN recognition system include not only P-450p but also one or more UDP-glucuronosyltransferases.

Animals↗