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PubMed1985

Differential effects of thioridazine, clozapine and metoclopramide on the induction of adrenomedullary enzymes by apomorphine.

The induction of two adrenomedullary enzymes, ornithine decarboxylase and tyrosine hydroxylase, by apomorphine was studied in rats receiving dopamine antagonists known to by specific in their site of action. Metoclopramide, a drug that acts predominantly on the A9 dopamine system, was effective in blocking the induction of the two enzymes by apomorphine. Thioridazine and clozapine, two antipsychotic drugs that act preferentially on the A10 dopamine systems, did not impair this induction and possibly potentiated it. The results suggest that the site of action of apomorphine responsible for the induction of adrenomedullary ornithine decarboxylase and tyrosine hydroxylase is located in the striatum.

Adrenal Medulla↗
PubMed1984

Pseudomonas aeruginosa beta-lactamase as a defence against azlocillin, mezlocillin and piperacillin.

Azlocillin, mezlocillin and piperacillin are weak substrates for the chromosomal beta-lactamase of Pseudomonas aeruginosa, and hydrolysis kinetics were calculated. Enzyme function in the living cell was studied by comparing antibiotic activity against a typical Ps. aeruginosa strain with inducible beta-lactamase expression with antibiotic activity against beta-lactamase uninducible and constitutive mutants. The inducible organism was less sensitive than its uninducible mutant to all three agents; this difference was more apparent at high inocula than low and in broth than in agar. These differences involved both enzyme induction and selection of genotypically enzyme derepressed variants. The penicillins were not, however, efficient beta-lactamase inducers at low concentrations and their activity against the inducible organism was antagonized by more potent inducers. Secondary inducers did not antagonize antibiotic activity against beta-lactamase uninducible and constitutive organisms. The beta-lactamase constitutive mutants were highly resistant to the three antibiotics tested.

Azlocillin↗
PubMed2005

Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways.

Drug-metabolizing enzymes and transporters are key factors that affect disposition of xenobiotics. Phase I enzyme induction by classes of microsomal enzyme inducers occurs via activation of transcription factors such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARalpha), and nuclear factor erythroid 2-related factor 2 (Nrf2). However, regulation of organic anion-transporting polypeptide (Oatp) uptake transporters by these factors is poorly understood. Hepatic Oatp uptake of some chemicals must occur prior to biotransformation; thus, we hypothesize that expression of Oatps and biotransformation enzymes is coordinately regulated in liver. In the present study, the effects of known chemical activators of AhR, CAR, PXR, PPARalpha, and Nrf2 on the hepatic mRNA expression of mouse Oatps and drug-metabolizing enzymes were quantified by the branched DNA assay. All chemicals increased the expression of their well characterized target drug-metabolizing enzymes: AhR ligands increased Cyp1A1, CAR activators increased Cyp2B10, PXR ligands increased Cyp3A11, PPARalpha ligands increased Cyp4A14, and Nrf2 activators induced NAD(P)H:quinone oxidoreductase 1. AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyl 126, and beta-naphthoflavone) increased Oatp2b1 and 3a1 mRNA expression in liver. CAR activators [phenobarbital, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, and diallyl sulfide] decreased Oatp1a1 mRNA expression. Two PXR ligands [pregnenolone-16alpha-carbonitrile (PCN) and spironolactone] increased Oatp1a4 mRNA expression in liver, whereas PXR ligands (PCN, spironolactone, and dexamethasone) and PPARalpha ligands (clofibrate, ciprofibrate, and diethylhexylphthalate) decreased Oatp1a1, 1b2, 2a1, and 2b1 mRNA expression in liver. Nrf2 activators (oltipraz, ethoxyquin, and butylated hydroxyanisole) down-regulated Oatp1a1 but up-regulated Oatp2b1 mRNA expression. Therefore, only a few transcription factor activators increased Oatp expression, and, surprisingly, many decreased Oatp expression.

Animals↗
PubMed1980

Cytochemical investigation on acid phosphatase activity in cerebral arteries in spontaneously hypertensive rats.

Acid phosphatase activity in the cerebral arterial system in spontaneously hypertensive rats (SHR) was cytochemically investigated. In the endothelial and medial smooth muscle cells, endoplasmic reticulums and Golgi complex revealed an intense acid phosphatase activity and primary lysosomes containing the high enzyme activity were found to be augmented in number. The enzyme activity was demonstrated in the vacuolated secondary lysosomes and in the intercellular spaces of the arterial walls. Lytic changes of the arterial mural cells and vessel matrix due to lysosomal enzymes were also evident. Causes of the lysosomal enzyme induction and roles of the enzyme in the developmental mechanism of hypertensive cerebrovascular changes in the SHR brain are discussed.

Acid Phosphatase↗
PubMed1971

Altered calcium metabolism in epileptic children on anticonvulsants.

A survey of 105 epileptic children aged 10-16 years at a residential school who were taking anticonvulsant drugs showed reduced serum calcium levels in 30% and a raised serum alkaline phosphatase in 24%. Urinary D-glucaric acid excretion, a quantitative index of hepatic enzyme induction, was raised in 94% of the children, and statistical analysis showed a significant inverse correlation with the level of serum calcium. These findings give further support for the view that an important factor in the development of the hypocalcaemia and occasional clinical osteomalacia in epileptics on anticonvulsant drugs is an alteration of vitamin-D metabolism in the liver as a result of microsomal enzyme induction. As a consequence there is an increased requirement for vitamin D which may not be met by average intakes in Britain.

Adipates↗
PubMed1990

Effect of antipyrine and phenobarbital on renal gamma-glutamyltransferase excretion in human urine.

Serum gamma-glutamyltransferase is used as a marker of hepatic enzyme induction. The kidney contains high activities of gamma-glutamyltransferase in the brush border membrane of the proximal tubule, from which it is released into urine. This study investigated the effect of phenobarbital and antipyrine, two inducers of hepatic monoxygenases and gamma-glutamyltransferase, on the urinary excretion of renal gamma-glutamyltransferase. Three groups (n = 6) of healthy male volunteers received 100 mg phenobarbital for 7 and 14 days and 1200 mg antipyrine for 7 days, respectively. Antipyrine and phenobarbital increased antipyrine elimination, serum gamma-glutamyltransferase, and the urinary excretion of renal gamma-glutamyltransferase, whereas urinary beta-N-acetylglucosaminidase, beta-glucuronidase, and total protein and glucose excretion were unchanged. No correlation was found between serum and urinary gamma-glutamyltransferase or both enzymes and antipyrine elimination. Increases in antipyrine elimination were positively correlated to increases in serum, but not urinary gamma-glutamyltransferase. The findings suggest that antipyrine and phenobarbital increase urinary gamma-glutamyltransferase excretion. However, the increase in urinary gamma-glutamyltransferase does not reflect the magnitude of hepatic enzyme induction.

Adolescent↗
PubMed1990

A physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.

A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Sprague-Dawley rat. This description included blood, liver, fat, muscle/skin, and visceral tissue groups. On the basis of other literature, the liver compartment was modeled to include two TCDD-binding sites, corresponding to a cytosolic receptor and a microsomal binding protein. A pharmacodynamic description was developed in which microsomal enzyme induction, both of arylhydrocarbon hydroxylase activity and of the amount of the microsomal TCDD-binding protein, was linked to fractional occupancy of the cytosolic receptor. This description was then used to analyze previously published data on TCDD disposition. The dissociation constant of the cytosolic Ah receptor (KB1) in vivo was estimated to be 15 pM by fitting enzyme induction data from McConnell et al. (1984). The ratio of liver to fat concentration of TCDD (about 4:1) was found to be primarily determined by the dissociation constant of the microsomal binding protein (7 nM) and the basal and induced concentration of this protein in the liver (25 and 200 nmol/liver, respectively). With these parameter values, the tissue distribution of TCDD in fat and liver, the two primary sites of accumulation, was accurately described following either single or repeated dosing with TCDD in the rat. The pharmacokinetic behavior described by the model was extremely sensitive to binding affinities, and only moderately sensitive to binding capacities in the dose range studied. Induction of microsomal TCDD-binding proteins was necessary in order to account for the differences in disposition at low (0.01 microgram/kg) and high (1.0 microgram/kg) daily doses of TCDD. Since the tumorigenicity of TCDD in rats is believed to be correlated with the biological responses of the Ah-TCDD complex, the present physiological pharmacokinetic description, which contains information on receptor occupancy at various dose levels, provides a plausible mechanistic connection for devising pharmacodynamic models which predict the cancer risk of TCDD in the rat.

Animals↗
PubMed1992

Effects of aging on gene expression of acetyl-CoA carboxylase and fatty acid synthase in rat liver.

After refeeding a fat-free diet to fasted rats, the time courses of transcriptional rates, mRNA concentrations, and enzyme induction of hepatic acetyl-CoA carboxylase and fatty acid synthase were compared between 1.5- and 18-month-old rats. In the old rats, the levels were mostly 40-70% of those in the young animals. Moreover, the peaks of the levels tended to be delayed in the old animals. The transcriptional rates were increased within only 1 h after the refeeding in the young animals, but not until 6 h in the old. The mRNA concentrations reached maximum at 16 h in the young rats, but at 24 h in the old. In the old rats, the incorporation of [3H]leucine into the enzyme proteins was also decreased roughly in proportion to the enzyme induction. The mRNA concentrations in the liver polysomes were roughly proportional to the total mRNAs. Thus, the translational activities did not appear to be altered by aging. It is suggested that the age-dependent decreases of acetyl-CoA carboxylase and fatty acid synthase induction can be mainly ascribed to the transcriptional steps.

Acetyl-CoA Carboxylase↗
PubMed1986

The cytosolic receptor binding affinities and AHH induction potencies of 29 polynuclear aromatic hydrocarbons.

The dose-response rat hepatic cytosolic receptor-binding avidities, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction potencies in rat hepatoma H-4-II E cells in culture were determined for 29 polynuclear aromatic hydrocarbons. It was apparent that the magnitude of the EC50 values for these in vitro responses were strongly dependent on structure. Dibenz[a,h]anthracene (1.6 X 10(-8) M), 7-methylbenz[a]anthracene (1.6 X 10(-8) M), 3-methylcholanthrene (2.8 X 10(-8) M) and picene (4.5 X 10(-8) m) exhibited the highest affinity for the receptor protein and these compounds were only 5-fold less active the 2,3,7,8-tetrachlorodibenzo-p-dioxin (1 X 10(-8) M). All of the compounds which were active in the receptor-binding and monooxygenase enzyme-induction assays possessed one common structural feature, namely the presence of a phenanthrene structure fused with at least 1 benzo ring. The results also demonstrated that there was not any apparent correlation between the receptor-binding avidities and in vitro monooxygenase enzyme-induction potencies for the most active polynuclear aromatic hydrocarbons.

Animals↗
PubMed1987

Plasma gamma glutamyltransferase levels during rifampicin therapy for tuberculosis.

A possible effect of rifampicin enzyme induction on microsomally derived plasma gamma glutamyltransferase (gamma GT) during treatment for tuberculosis patients with spinal bone disease and pulmonary or lymph node involvement was studied. Of 10 patients with bone disease 5 had raised levels prior to therapy (greater than 60 IU/l) and none were alcohol consumers. Gamma GT is not known to be present in bone and this probably represents an indirect effect on the liver. Changes in gamma GT in the first 2 months of rifampicin/isoniazid treatment were variable and will not serve as an index of response to therapy. Of 69 patients with lung or lymph node disease 15 had raised levels during treatment and 9 had a high alcohol intake, when the alcohol group were excluded there was no significant difference from controls who had completed treatment (p greater than 0.1). We conclude that plasma gamma GT, a standard clinical estimation of liver dysfunction, is a useful index of suspicion for alcoholics among the tuberculous group but the disease itself can produce similar levels. It did not reflect the known hepatic microsomal inducing properties of rifampicin and thus differs from the anticonvulsant model. Clinical value would be enhanced if specific liver isoenzymes in plasma were identified which separated tissue injury, enzyme induction and the effect of extrahepatic infection on the liver.

Enzyme Induction↗
PubMed1985

Genetic differences in oxygen toxicity are correlated with cytochrome P-450 inducibility.

Susceptibility to oxygen toxicity was studied in three inbred and two hybrid strains of mice. Because in vitro studies have shown that the cytochrome P-450 enzymes can produce oxygen radicals and H2O2, we tested the hypothesis that inducibility of these enzymes might play a role in oxygen toxicity. Mice responsive to hepatic microsomal enzyme induction by aromatic hydrocarbons [C3H/HeJ, C3H/HeN, C3H/HeJ X DBA/2J (designated C3D2F1/J), C3H/HeN X DBA/2J (designated C3D2F1/N)] were more sensitive to the toxic effects of 100% oxygen exposure than were genetically unresponsive mice (DBA/2J). DBA/2J mice survived significantly longer exposure periods with less lung damage. Lung and liver cytochrome P-450 levels increased 2-to 3-fold in C3H and F1 mice during 100% oxygen exposure (maximum levels at 72-96 hr) and subsequently fell prior to death. No increases were seen in cytochrome P-450 levels in DBA/2J mice. Metabolic pathways involving cytochrome P-450 enzymes may initiate or modulate oxidative damage due to oxygen radicals. The difference in responsiveness of mice to microsomal enzyme induction may imply genetic differences in susceptibility to oxidative stress, may help to explain species differences in susceptibility, and may have long-term implications in therapeutics and patient care if similar inherited differences exist in humans.

Animals↗
PubMed1993

Age-dependent basal level and induction capacity of copper-zinc and manganese superoxide dismutase and other scavenging enzyme activities in leukocytes from young and elderly adults.

Several enzymes, including superoxide dismutase (SOD), catalase, glutathione peroxidase, and D-glucose-6-phosphate dehydrogenase are capable of scavenging reactive oxygen species in in vivo. We assessed both basal levels and the capacity of these enzyme activities to be induced in human leukocytes in response to a variety of agents. Basal activity of copper-zinc SOD, and manganese SOD showed little variation with age. In contrast, the basal activity of the three H2O2 scavenging enzymes, catalase, glutathione peroxidase, and D-glucose-6-phosphate dehydrogenase, was significantly higher in younger adults than in elderly individuals. Both manganese SOD and copper, zinc SOD activities were significantly induced by paraquat, interleukin-1, tumor necrosis factor, adriamycin, and bleomycin in lymphocytes and neutrophils from asymptomatic non-aged adults, whereas neither activity was induced in aged individuals. In contrast, glutathione peroxidase activity was significantly induced in both groups of subjects, whereas catalase and D-glucose-6-phosphate dehydrogenase were only slightly induced in either. Enzyme induction with paraquat, adriamycin, or bleomycin was inhibitable by neutralizing antibody to interleukin-1 and tumor necrosis factor, suggesting that the inductions observed with these three drugs are due to the distal mediators, interleukin-1 or tumor necrosis factor released from the cells. Finally, as observed in the regulation of genes in eukaryotes (Storz et al: Bacterial defenses against oxidative stress. Trends Genetics 1990, 6:363-368, ref. 1) O2- and H2O2 seem to differ in the rate of change with age in both basal levels and inducibility under oxygen stress.

Adolescent↗
PubMed1985

Methylprednisolone half-life during simultaneous barbiturate treatment and mechanical hyperventilation of neurosurgical patients.

The pharmacokinetics of methylprednisolone sodium succinate (MP) were studied in six neurosurgical patients under intensive treatment with large doses of MP, barbiturates, and mechanical hyperventilation. The study showed a remarkable level of enzyme induction within 24 hours after starting treatment, when the first blood samples were taken. The half-life (t 1/2) for MP during barbiturate and hyperventilation therapy was found to be reduced by a mean 55% (p less than 0.01) in relation to the t 1/2 of MP when administered alone. Studies on the day after termination of barbiturate intake indicated a tendency for an increase in the t 1/2 of MP, but it was not significantly different from the pretermination assessment (p greater than 0.05). On the basis of this study it is not possible to determine if the change in t 1/2 alone is governed by enzyme induction or by a combination of this plus a change in the distribution and clearance of the steroid. The clinical implication of these findings is that patients who are undergoing steroid treatment and at the same time are sedated with barbiturates should have their MP dose increased in order to compensate for the marked reduction of t 1/2 of MP.

Adolescent↗
PubMed1995

Nicotine and cotinine accumulation in pigmented and unpigmented rat hair.

This study was performed to assess the contribution of systemic and external uptake to nicotine accumulation in hair. The systemic nicotine uptake in hair was determined in pigmented rats (Brown Norway) and albino rats (Sprague-Dawley) after subcutaneous administration of 3 doses of nicotine with osmotic minipumps [5, 10, and 20 mg/(kg x day) for 3 weeks], the highest dose also following metabolic enzyme induction. The external nicotine uptake was determined in cut hair of both strains after exposure to room-aged cigarette sidestream smoke, a surrogate for environmental tobacco smoke (nicotine concentration: 5 micrograms/liter for 1, 2, and 3 weeks). Nicotine and its metabolite cotinine were determined using capillary GC after complete alkaline digestion of the hair sample and solvent extraction. Systemic uptake: Nicotine and cotinine concentrations in hair were dose-dependent and correlated with plasma concentrations. The nicotine concentration was approximately 20 times higher in pigmented than in unpigmented hair. The cotinine concentration was approximately 10 times lower than the nicotine concentration in pigmented hair. After enzyme induction before administration, nicotine and cotinine concentrations in hair were significantly reduced in parallel to the reduced plasma concentrations, showing the influence of metabolism. External uptake: Nicotine was found in the hair of both strains, the concentration in pigmented hair being a factor of 1.5 higher than in unpigmented hair. Thus, hair pigmentation had a major influence on systemic uptake in hair and a minor influence on external uptake in hair.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Induction of 1-cys peroxiredoxin expression by oxidative stress in lung epithelial cells.

1-Cys peroxiredoxin (1-cysPrx), a member of the peroxiredoxin family that contains a single conserved cysteine residue, reduces a broad spectrum of hydroperoxides. We studied changes in 1-cysPrx expression in rat lungs and lung cell lines in response to oxidative stress due to hyperoxia, H2O2, or paraquat. After 60 h of hyperoxia (>95% O2), mRNA and protein levels of 1-cysPrx and peroxidase activity were significantly elevated in rat lungs by approximately 1.5- to 2-fold compared with the control (P < 0.05). A similar induction of 1-cysPrx was observed in mouse lungs following exposure to O2 for 63 or 72 h; enzyme induction in mouse lungs was similar for wild-type and glutathione peroxidase 1 gene-targeted mice. H2O2 and paraquat treatment induced 1-cysPrx gene expression in L2 cells. Enzyme induction was attenuated by pretreatment with Trolox or N-acetylcysteine. Actinomycin D treatment showed that stability of 1-cysPrx mRNA was not altered in the presence of H2O2 or paraquat, indicating that increased expression with oxidative stress is regulated at the transcriptional level. These data indicate that the antioxidant enzyme 1-cysPrx is induced in lung cells by oxidative stress.

Animals↗
PubMed1995

Effect of type of dietary fat and ethanol on antioxidant enzyme mRNA induction in rat liver.

We carried out a study to relate the effect of the type of dietary fat and ethanol on antioxidant enzyme mRNA levels in liver in the intragastric feeding rat model. Different types of dietary fat were administered [saturated fat (SE), corn oil (CE) and fish oil (FE)] with ethanol to induce varying severities of liver injury. Ethanol-fed rats were pair-fed with dextrose-fed controls that received isocaloric amounts of dextrose. All animals were killed at 1 month and the following studies were carried out: evaluation of severity of pathologic liver injury, mRNA quantitation for catalase, glutathione peroxidase (GPx), and manganese superoxide dismutase (MnSOD), microsomal conjugated dienes, and hydrogen peroxide. SE animals had no liver injury, FE animals had severe liver injury, and CE animals had moderate liver injury. Ethanol induced GPx mRNA in all dietary groups, with the highest levels seen in the FE group. The pattern of catalase mRNA induction was similar to that of GPx mRNA. In contrast, MnSOD mRNA was decreased compared to controls in animals that developed pathologic liver injury, i.e., CE and FE groups. A positive correlation was seen between conjugated diene levels and GPx mRNA (r = 0.88, P < 0.01) and catalase mRNA. The similar slopes for the relationship between conjugated dienes and catalase in the fish oil and non-fish oil groups indicate that the same degree of lipid peroxidation increases catalase mRNA to a greater degree in fish oil-fed rats. A positive correlation was also seen between catalase mRNA and H2O2 (r = 0.95, P < 0.001).

Animals↗
PubMed1993

Confounding factors in biological monitoring of exposure to organic solvents.

Some environmental and physiological factors that affect the toxicokinetic behaviors of organic solvents were examined using a physiologically based pharmacokinetic model developed for trichloroethylene (TRI). The conclusions are as follows: 1) Body fat content substantially affects the kinetic behavior of TRI: the TRI concentration in blood and the urinary excretion rate of its metabolites are higher in slim men than in obese men during exposure, but these parameters eventually become higher in obese men. 2) There is a sex difference in the pharmacokinetic profiles of TRI. Although retention of TRI in the body is greater in men than in women, the blood concentration of TRI in women is higher than in men 16 hours after exposure. 3) Because of increased pulmonary ventilation and cardiac output, physical activity (workload) during exposure greatly increases the blood concentration of TRI and the urinary excretion of its metabolites, whereas the activity after exposure has only a marginal influence. 4) Ethanol-induced inhibition of TRI metabolism causes a marked change in the kinetic behavior when the TRI exposure level is low, whereas enzyme induction by ethanol significantly affects the kinetics only when the exposure concentration is high. The effect of enzyme induction differs from compound to compound. Whether the compound concerned is a perfusion-limited substrate (TRI, for example) or a capacity-limited substrate (1,1,1-trichloroethane, for example) determines the extent of the effect. 5) Metabolic interaction between solvent vapors inhaled simultaneously may not become apparent until the exposure level increases to a degree that will overload the enzyme capacity.

Alcohol Drinking↗
PubMed1987

Antioxidant enzymes and survival of normal and simian virus 40-transformed mouse embryo cells after hyperthermia.

Relative cell survival and activity of the free radical scavenging enzymes superoxide dismutase, catalase, and glutathione peroxidase were measured in cloned normal (MEA) and SV40-transformed (SVMEA) mouse embryo cells exposed at 44 degrees C for 0-3 h. At 37 degrees C, all three enzymes were 2-5 times higher in MEA than in SVMEA. Hyperthermia did not significantly alter enzyme levels in either cell line but selectively reduced transformed cell survival to less than 5% while relative survival of normal cells remained above 75%. The latter, however, could be reduced to 25% when normal cells were pretreated with 3 mM diethyldithiocarbamate, an inhibitor of copper- and zinc-containing superoxide dismutase. Similar treatment rendered SVMEA extremely thermosensitive. On the other hand, sublethal heat treatment (15 min at 45 degrees C) of cultured cells resulted in a relative thermal resistance upon subsequent exposure to 45 degrees C for 1-4 h. This induced thermotolerance was associated with a rise in antioxidant enzyme levels and both became significant only 4-6 h after the initial heat treatment. Induced enzyme and thermotolerance levels in transformed cells remained, nonetheless, far below those of normal cells. The data show that inherent (in MEA) as well as induced (in SVMEA) thermotolerance is associated with high antioxidant enzyme levels while the reverse is true in the case of inherent (in SVMEA) and induced (in MEA) thermosensitivity. These findings suggest that increased production of oxygen free radicals may be involved in hyperthermic cell injury, which then becomes a function of basal or inducible levels of antioxidant enzymes. Induction of the latter by hyperthermia is apparently inefficient in transformed cells making them more vulnerable. Enzyme induction seems also to require a lag period of 4-6 h suggesting the possible involvement of an intermediate inducer(s) at molecular level. The so-called heat shock proteins may be candidates for such a role.

Animals↗