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PubMed1989

2(3)-tert-butyl-4-hydroxyanisole inhibits oxidative metabolism of aflatoxin B1 in isolated rat hepatocytes.

Previous studies indicate that dietary administration of phenolic antioxidants, 2(3)-tert-butyl-4-hydroxyanisole (BHA) and 3,5-di-tert-butyl-4-hydroxytoluene, inhibits the carcinogenic effect of a number of chemical carcinogens including aflatoxin B1 (AFB1). Induction of hepatic enzymes, such as glutathione S-transferase, UDP-glucuronyltransferase, and epoxide hydrolase, has been shown to be responsible for the reduction of AFB1 cytotoxic and carcinogenic effects. The effect of BHA on AFB1 activation was examined in vitro utilizing isolated rat hepatocytes and liver microsomes. In hepatocytes, the total AFB1 content and bound form of AFB1 were 3.4 and 1.4 pmol/10(6) cells, respectively. In the cell-free microsomal activating system, 2.2 pmol were activated per mg of microsomal protein during 60 min of incubation. BHA (0.1-0.5 mM) inhibited AFB1 activation and binding in both systems in a dose-dependent manner; in hepatocytes, 90% inhibition was observed at 0.5 mM. Analyzing various AFB1 adducts, BHA (0.25 mM)-treated hepatocytes contained a significantly reduced amount of AFB1 macromolecular adducts. The antioxidant neither stimulated nor inhibited the cytosolic glutathione S-transferase and microsomal UDP-glucuronyltransferase activities. Analysis of various hydroxylated (aflatoxins M1 and Q1 (AFM1 and AFQ1] and demethylated (aflatoxin P1 (AFP1] metabolites of AFB1 in both the conjugated and unconjugated form indicated that there was a 30-50% reduction of unconjugated AFP1, AFQ1, and AFM1, whereas AFB1 was increased 3-fold. There was no significant change of conjugated metabolites. The effect of BHA on AFB1 activation in hepatocytes was compared with that of other cytochrome P-450 inhibitors; the ED50 values of SKF 525A, BHA, and metyrapone were 9 microM, 40 microM, and 280 microM, respectively. In the cell-free microsomal system, biotransformation of AFB1 to AFP1, AFM1, and AFQ1 was also inhibited. Kinetic analysis of p-nitroanisole O-demethylase activity of rat liver microsomes demonstrated that BHA inhibited noncompetitively with an apparent Ki of 90 microM. In the absence of enzyme induction, the phenolic antioxidant, BHA, blocks the oxidative biotransformation of AFB1 in isolated hepatocytes.

Aflatoxin B1↗
PubMed1980

Hepatic drug metabolism and anesthesia.

Anesthetic agents, including most inhalation anesthetics, the barbiturates, narcotics, local anesthetic amides and curare-like compounds are metabolized inside the liver cell. Consequently, drug metabolism in the liver has become an increasingly important consideration in the practice of anesthesiology. Hepatic metabolism is, first and foremost, a mechanism that converts drugs and other compounds into products that are more easily excreted and that usually have a lower pharmacologic activity than the partent compound. Thus, duration and intensity of drug action are limited. However, there are exceptions. In certain instances a metabolite may have higher activity and/or greater toxicity than the original drug. Intrahepatic metabolism hinges upon the oxidative reactions that are catalyzed by a group of mixed oxidases, the P-450 cytochromes. Their concentration and activity can be enhanced by certain drugs or environmental chemicals that are ingested by the individual. This usually is beneficial, in that this mechanism of enzyme induction promotes the detoxification of pharmaca, which is the normal aspect of drug metabolism. If, however, the normal metabolite is more toxic than the parent compound, or there exists an alternate, abnormal metabolic pathway that produces a toxic metabolite, then enzyme induction may have serious consequences. Inorganic fluoride is a normal metabolite of methoxyflurane. It is responsible for the high-output renal failure that can be observed after anesthesia with this inhalation agent. A patient with induced enzyme activity is especially at risk to develop methoxyflurane-related renal failure. The picture of halothane toxicity is not as clear. There are indications that an abnormal metabolite, produced in sufficient quantities via an alternate pathway with induced enzyme activity, may be capable of causing liver damage.

Acute Kidney Injury↗
PubMed1983

The glucagon-insulin antagonism and glucagon-dexamethasone synergism in the induction of phosphoenolpyruvate carboxykinase in cultured rat hepatocytes.

In hepatocytes precultured for 24 h with dexamethasone glucagon increased phosphoenolpyruvate carboxykinase activity 3-4-fold with a half maximal activity increase at 30 pM. The half maximal effective glucagon concentration was enhanced 10-fold to 300 pM when insulin was added simultaneously. The glucagon-insulin antagonism was maximally expressed when glucagon was present at low physiological concentrations. At equimolar doses it was only in the concentration range around 0.1 nM that glucagon and insulin became powerful antagonists; at higher levels glucagon was the dominant hormone. In hepatocytes not pretreated with dexamethasone glucagon still enhanced phosphoenolpyruvate carboxykinase activity, but the half maximal effective dose raised more than 30-fold to 1 nM. The degree of stimulation, however, remained essentially unchanged. Thus dexamethasone shifted the glucagon sensitivity of the cells into the physiological concentration range; it exerted a half maximal effect at 10 nM. Dexamethasone was not required for the enzyme induction proper if the cells had been pretreated with the glucocorticoid. The amount of the glucagon-stimulated enzyme induction was dependent on the time period of cell pretreatment with dexamethasone. Glucagon enhanced enzyme activity to the same constant suboptimal level irrespective of whether cells had been pretreated with glucocorticoid for 1 or for 14 h. If cells were pretreated for more than 15 h, glucagon linearly increased enzyme activity further until the maximal value was reached after 24 h pretreatment. The glucagon-insulin antagonism and the glucagon-glucocorticoid synergism were observed at physiological hormone concentrations indicating that the interaction should be effective also in vivo. Dexamethasone does not seem to be generally permissive for the inducing action of glucagon, but rather sensitizes the cell towards lower physiological hormone concentrations.

Animals↗
PubMedDate not supplied

[Effect of adrenaline, hydrocortisone and serum HDL lipoproteins on the activity of multiple forms of glucose-6-phosphate dehydrogenase in the rat liver].

A decrease in activity of glucose-6-phosphate dehydrogenase (G6PD) in Wistar rat liver tissue, caused by stress, was realized via a mechanism, involving adrenaline and hydrocortisone as first messengers and cAMP as a second messenger. In these systems G6PD II and IV isoenzymes were mainly inhibited. These are the urgent mechanisms for regulation of the enzymatic activity. Activation of G6PD within the reparative period after the stress was due to induction of the enzyme synthesis. Cooperative action of adrenaline, hydrocortisone and high density lipoproteins from blood serum, modulating the effect of adaptive hormones, was responsible for the enzyme induction. Actinomycin D and vinblastine (inhibitor of the cell microtubular apparatus) prevented the stimulation of G6PD isoenzymes caused by the cooperative hormonal effect. The data obtained suggest that the cooperative effect occurred as a result of lysosomes translocation to nucleus and the subsequent activation of chromatin.

Animals↗
PubMed2002

Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: insights into the measurement of hepatic cytochrome P450 1A2 induction.

OBJECTIVE: The correct in vivo quantification of aryl hydrocarbon receptor-mediated induction of cytochrome P450 1A2 (CYP1A2) in humans is a long-standing question. We compared the performance of several modifications of the caffeine test for measurement of CYP1A2 activity in subjects with exceptionally high, low, or absent enzyme induction. METHODS: CYP1A2 activity was measured in 2 women highly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in 1 man moderately exposed, and in 50 control subjects (30 nonsmokers and 20 heavy smokers). After the application of a test dose, caffeine demethylation was detected with the carbon 13 breath test, the total clearance, and several serum and urinary metabolite ratios. RESULTS: In the highly TCDD-exposed persons, results of the breath test (cumulative 15-minute dose), the total caffeine clearance, the serum metabolic ratio paraxanthine/caffeine (30 and 120 minutes after application), and the urinary metabolic ratio sum of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methyluric acid (1U), and 1-methylxanthine (1X) over 1,7-dimethyluric acid (17U) showed a CYP1A2 activity 8 to 10 times higher than the mean of nonsmokers. In contrast, two caffeine urinary metabolic ratios with the parent substance in the denominator did not reflect the CYP1A2 enzyme induction. These ratios strongly depended on urine flow. For the breath test, only results evaluated for a short sampling period (eg, 15 minutes after application) revealed the high induction. Compared with nonsmokers, higher mean values (maximally 1.8 times) were observed in smokers with all tests. CONCLUSION: After high TCDD exposure, hepatic CYP1A2 activity is inducible at least 10 times in humans. Moderate TCDD exposure (up to 1000 ppt in blood fat) does not cause a CYP1A2 induction that can be measured to differentiate from background exposure individually. Therefore direct quantification of such toxins is more specific and sensitive.

Adult↗
PubMed2001

Kinetics and inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) in rats.

The kinetic properties and the inductive potency of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (H7CDD) were studied in Wistar rats following subcutaneous (s.c.) injections. For assessing the dose-response, rats were treated with a single dose of 3. 10 or 30 microg H7CDD/kg body wt. Tissue concentrations and enzyme induction were measured 1, 2, and 3 weeks after treatment, and in the 30 microg/kg group additionally after 6, 20 and 57 weeks. Tissue concentrations increased dose-dependently from 3 to 30 microg/kg. Concentrations in liver were always higher than in adipose tissue, the concentration ratio: liver/adipose tissue varied between 32 and 67. The activity of (ethoxyresorufin O-deethylase) (EROD) in liver microsomes was clearly induced by H7CDD, reaching maximal induction three weeks after treatment. (3-fold at 3 microg/kg, 5-fold at 10 microg/kg and nearly 30-fold at 30 microg/kg). For assessing the time dependency, tissue levels and hepatic enzyme induction were monitored over a period of 57 weeks after a single s.c.-injection of 30 microg H7CDD/kg body wt. Hepatic concentrations of the congener remained rather constant from the 2nd to the 20th week after treatment (280 ng/g and 319 ng/g, respectively). In contrast, concentrations in adipose tissue and thymus increased 2-fold during this period, and 20 weeks after injection reached a maximum of 11 ng/g and 3 ng/g, respectively. Thereafter, the concentrations decreased and tissue levels of 91 ng/g (liver), 3 ng/g (adipose tissue) and 2 ng/g (thymus) were detected 57 weeks after treatment. The elimination half-life (t 1/2) calculated from our data was 140 days in liver and 130 days in adipose tissue. The reasonable explanation for the increase in tissue concentrations of H7CDD up to 20 weeks after treatment is the slow release of this congener from the subcutaneous injection site. Induction of hepatic EROD activity always closely followed changes in the hepatic concentrations of H7CDD, reaching a maximum 3 weeks after treatment and remaining at this level until the 20th week. Correlation analysis of hepatic H7CDD concentrations versus the extent of EROD induction indicated a linear relationship in a double-logarithmic plot. When compared with TCDD, the hepatic monooxygenase-inducing potency of H7CDD within the low dose range was found in the rat to be 170 to 440-times lower than that of TCDD. Measurement of 14C-caffeine demethylation, using a 14CO2 breath test, revealed a similar time course in vivo when compared with the microsomal EROD activity ex vivo.

Animals↗
PubMed1985

Decreased protein synthesis of transforming lymphocytes from aged humans: relationship to impaired mitogenesis with age.

Recent studies have indicated that the decline in mitogenesis during the aging process may be related to intracellular defects that become apparent when the cells are subjected to the metabolic stress of cell transformation. We provide the first report of an age-related decline in protein synthesis in human lymphocytes exposed to phytohemagglutinin. This impairment in protein synthetic capacity from aged subjects' transforming cells is apparent from 24 to 72 h of culture. By 72 h of culture the incorporation of radiolabeled leucine in stimulated cells from elderly subjects is about half that for the young. However, cells from the aged have an increased protein content in the face of decreased synthesis suggesting a degradation defect. Since protein synthesis may be necessary for the induction of key effectors which activate glycolysis (which is necessary for transformation), we sought to relate the impaired protein synthesis to the impaired glycolytic enzyme induction with age. Cycloheximide totally inhibited glycolytic enzyme induction as well as cell transformation. A defect in protein synthesis with age may interfere with new enzyme synthesis which is necessary to activate requisite pathways for mitogenesis such as glycolysis.

Adult↗
PubMed1973

Erythrocyte catabolism by macrophages in vitro. The effect of hydrocortisone on erythrophagocytosis and on the induction of heme oxygenase.

Phagocytosis of erythrocytes was studied in vitro in an incubation system consisting of rat peritoneal macrophages and antibody-coated (59)Fe-labeled erythrocytes. The system was characterized in terms of the rate and magnitude of erythrophagocytosis, determined by the interiorization of the (59)Fe label. On incubation of 150 x 10(6) macrophages with 75 x 10(6) antibodycoated erythrocytes, erythrophagocytosis began within a few minutes and was essentially completed after 2 h when 50% of the offered red cells had been ingested by the macrophages. Heme oxygenase (HO) activity, which is very low in native macrophages, increased 4- to 10- fold in response to the ingested erythrocytes; this enzyme stimulation occurred with a delay of 3 h in relation to erythrophagocytosis. Actinomycin D or puromycin prevented the increase of HO activity without affecting erythrophagocytosis, which suggests that the enzyme stimulation was due to substrate-mediated enzyme induction. Hydrocortisone (HC) (0.1 mg/ml medium) dissociated erythrophagocytosis from HO induction, leaving the former unimpaired but completely suppressing the latter. The suppressive effect of HC on the enzyme induction was completely prevented by 5 mg glucose and 0.02 U insulin/ml of the medium. In macrophages engaged in erythrophagocytosis. HC also lowered glucose removal from the medium and reduced formation of (14)CO(2) from [1-(14)C]glucose. These results suggest that induction of HO in macrophages by the hemoglobin of ingested erythrocytes requires intact transport or metabolism of glucose. Glucose utilization appears to be impaired by HC, but is restored by additional glucose and insulin. The findings suggest that plasma steroid concentrations in the pharmacological range could reduce bilirubin formation in phagocytic cells in vivo without affecting the sequestration and degradation of erythrocytes. This provides a possible explanation for the observation that in patients with hepatogenous jaundice, steroids often lower the serum bilirubin level.

Animals↗
PubMed2004

Presence and induction of the enzyme NAD(P)H: quinone oxidoreductase 1 in the central nervous system.

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes a reductive detoxification that is thought to protect cells against the adverse effects of quinones and related compounds. NQO1 activity is present in all tissues. Absence of the enzyme produces abnormalities in the redox state and seizures, suggesting an important role of the protein in the central nervous system. Immunohistochemical analysis showed that the protein was found throughout the brain of the adult rat and mouse, with complete absence of the protein in brains from NQO1-/- mice. NQO1 was not seen in any neuronal population, but was localized to Bergmann glial in the cerebellum and a subset of the oligodendrocytes throughout the brain. Prolonged seizures induced in adult rats with kainic acid resulted in an increase in activity of the enzyme throughout the brain, most prominently in the cerebellum, but immunoreactivity did not appear in neurons. Comparison of the axons in the corpus callosum from a wild-type mouse to a knockout mouse showed that myelin is produced in the absence of NQO1, but there appears to be more small-diameter axons in the knockout animal. These results suggest that NQO1 has a role in myelination in the central nervous system or in the insulating/wrapping function of glial cells.

Animals↗
PubMed1982

Migration inhibitory action of bacterial lipopolysaccharide on progenitor cells of monocyte/macrophage lineage growing in culture in the presence of colony-stimulating factor (CSF-1).

Addition of lipopolysaccharide (LPS) to the culture of mouse myeloid stem cells (CFUc) increased the incidence of compact colonies and decreased that of dispersed ones in the presence of colony-stimulating factor (CSF-1) which had not such an effect by itself even in high concentrations. Although colony morphology was thus changed, nearly all colonies were composed of monocytes. The incidence of compact colonies increased with the increase of LPS concentration but plateaued at about 50%. Bone marrow cells of LPS-tolerant mice responded to LPS in vitro to a slightly decreased extent. The activity of LPS was decreased by alkaline or acid hydrolysis of the LPS molecule and inhibited by polymixin B, but not by indomethacin, alpha-L-fucose, nor by alpha-methyl-D-mannoside. Other immunopotentiating substances, such as OK-432, Lentinan, and Levamisole, had no effect on the colony morphology. Both muramyl dipeptide and poly(I).poly(C) were also ineffective. Furthermore, the action of LPS was not abolished by the use of heat-inactivated serum in the culture. LPS was no longer stimulative for the induction of lysosomal enzymes in the CSF-stimulated culture, although it greatly enhanced the enzyme induction in the unstimulated culture. These results indicate that the cells of monocyte/macrophage lineage develop the capacity for migration before they become responsive to LPS, and that the LPS-responding monocytic cells can proliferate even in a state of confluence induced by LPS.

Animals↗
PubMed1993

Induction of antioxidant enzymes and DT-diaphorase in human blood mononuclear cells by light stress.

Human blood mononuclear cells exposed to visible light increase their antioxidant enzyme (superoxide dismutase, catalase, and glutathione peroxidase) and DT-diaphorase activities. The activities of CuZn-superoxide dismutase (3.70 +/- 0.25 U/mg protein), catalase (4.60 +/- 0.39 U/mg protein), and DT-diaphorase (1.40 +/- 0.11 mumol DCPIP/min.mg protein) increased 1.5-fold when mononuclear cells were exposed at 38 W/m2 for 4 h. Se-containing glutathione peroxidase activity (6.76 +/- 0.21 mU/mg protein) increased 1.3 times after 3 h of exposure to 38 W/m2. Conversely, Mn-superoxide dismutase (2.20 +/- 0.20 U/mg protein), succinate dehydrogenase (0.86 +/- 0.04 mumol DCPIP/min.mg protein), and cytochrome oxidase (0.54 +/- 0.04 min-1 (k')/mg protein) activities remained constant during this period of exposure. The treatment of cells with cycloheximide prevented the response triggered by light exposure. These results introduce new insight to the adaptive response of human cells to light stress suggesting that: (a) the response observed might be ascribed to synthesis of stress proteins rather than to activation of a preexisting pool, and (b) that DT-diaphorase and CuZn-superoxide dismutase may operate biologically in a concerted fashion resulting in antioxidant activity.

Adult↗
PubMed2000

Induction of lytic enzymes by the interaction of Ustilago maydis with Zea mays tissues.

The nonpathogenic (FB-2) and pathogenic (FB-D12) strains of Ustilago maydis were grown in medium supplemented with different carbon sources including monosaccharides, polysaccharides, and plant tissues. Both strains were able to grow on all substrates, with doubling times varying from 2 to 25 h depending on the carbon source. Plant tissues supplied as carbon source induced lytic enzymes differentially; pectate lyase and cellulase activities were induced preferentially by apical stem meristem in strain FB-D12, whereas leaves preferentially induced xylanase and cellulase activities in strain FB2. Stems induced polygalacturonase activity in both strains. All enzyme activities, except cellulase in the FB-D12 strain, were detected at a low level when U. maydis was grown on glucose. In planta, chlorosis and production of teliospores were paralleled by an increase in pectate lyase activity. Anthocyanin production and formation of galls and teliospores correlated with polygalacturonase expression whereas cellulase activity increased only during the stage of anthocyanin production and gall formation. Expression of xylanase activity coincided with the last stage of teliospore formation.

Culture Media↗
PubMed1982

Induction of microsomal enzyme activity by flupenthixol in chronic schizophrenics.

The effect of long-term treatment with flupenthixol on hepatic microsomal enzyme activity was studied in 12 chronic schizophrenic outpatients who had been receiving two weekly maintenance doses for at least 6 months. Antipyrine half-life was measured in the 12 patients while they continued to receive the drug. Flupenthixol was then discontinued for 6 weeks and antipyrine half-life was repeated in 7 of the 12 patients. In the 12 patients the plasma antipyrine elimination half-life was 4-24 h (mean 9.73 +/- 1.61 h) when receiving flupenthixol and there was a significant negative correlation between antipyrine half-life and the dose of flupenthixol (r = 0.582, P less than 0.05). In the seven patients to whom antipyrine was given on two occasions, antipyrine half-life was 7.33 +/- 1.07 h and 12.04 +/- 1.87 h on and off flupenthixol treatment respectively. The clearance significantly decreased when flupenthixol was discontinued, but there was no change in the apparent volume of distribution.

Adult↗