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PubMed1987

Use of monoclonal antibodies to characterize the induction response of the cytochrome P-450-dependent mixed function oxidase system to nitrofluoranthenes.

In prior studies with neonatal rats we have suggested that nitrated polycyclic aromatic hydrocarbons (NPAH) are 3-methylcholanthrene (3-MC) type of inducers of cytochrome P-450. These observations have been extended by studying the effect of fluoranthene (FL) and its nitrated derivative, 3-nitrofluoranthene (3-NF) and a mixture of nitrated fluoranthenes (NFs) on the induction of hepatic and pulmonary monooxygenase activities in adult rats. We have characterized the effect of these compounds on hepatic cytochrome P-450 isozyme(s) using immunoblot analysis. The administration of 3-NF and NFs to rats resulted in highly significant induction (1.9- to 5.8-fold) of hepatic and pulmonary aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin-O-deethylase (ERD) activities. FL was either ineffective or much less effective in inducing these enzyme activities. The enzyme induction response to these compounds occurred in the following order: NFs greater than 3-NF greater than FL. SDS-PAGE of hepatic microsomes prepared from FL-, 3-NF- and NFs-treated animals revealed a higher content of protein migrating in the P-450 region. Characterization of isozymes of P-450 was carried out by Western blot analysis with highly specific monoclonal antibodies (MAb) raised against 3-MC-specific P-450 (MAb 1-7-1) and phenobarbital-specific P-450 (MAb-2-66-3) isozymes. Hepatic microsomes prepared from 3-NF- and NFs-treated rats showed two distinct immunoprecipitin bands with MAb 1-7-1 whereas microsomes prepared from FL-treated animals showed a sharp band with MAb 2-66-3. MAb 1-7-1 significantly inhibited (approximately 80%) AHH activity induced by 3-NF and NFs. On the other hand FL-induced AHH activity was only moderately (approximately 30%) inhibited by MAb 1-7-1 whereas higher inhibition (approximately 60%) was observed with MAb 2-66-3. Analysis of BP metabolites by h.p.l.c. revealed enhanced production of metabolites by liver microsomes from 3-NF- and NFs-treated animals. The formation of BP 7,8-diol was 1.8- to 2.4-fold increased following treatment of animals with 3-NF and NFs respectively. Addition of MAb 1-7-1 to a microsomal mixture from 3-NF- and NFs-treated rats inhibited the formation of BP phenols (60-75%) and BP 7,8 diol (52-60%). These inhibitory effects were not observed with microsomes prepared from FL-treated rats. These studies suggest that NFs induce specific monooxygenases in liver and that they are inducers of P-450 isozymes c and d.

Animals↗
PubMed1997

Cytotoxicity and biotransformation inducing activity of rodent beddings: a global survey using the Hepa-1 assay.

Unknown and uncontrolled toxic materials in the environment of experimental animals endanger the reliability of research results. In this study, the cytotoxic and biotransformation inducer activity of beddings obtained from a number of institutes in Africa, Americas, Asia, Australia and Europe were compared using the Hepa-1 in vitro-assay. A great variation in both cytotoxicity and inducer activity was observed. Pine shavings beddings, commonly used all over the world appeared in general to be highly cytotoxic. Extracts of corn cob, rice hulls and straws, used in a few laboratories, were practically non-toxic. Some softwood extracts, especially from pine, were also potent inducers of cytochrome P4501A1. Grass as well as hardwood materials were much less active. Due to great variation in toxicity and inducer activity in the beddings it is possible that, in spite of standardization of feed and other environmental factors, different biological responses to chemicals and drugs in even genetically identical animal strains in different laboratories, may be obtained. Control of bedding, one of the animals' closest environmental factors, for its toxicity and biotransformation enzyme induction is strongly recommended.

Animals↗
PubMed1996

Pharmacokinetics of new antiepileptic drugs.

This article surveys the pharmacokinetic parameters for the new antiepileptic drugs (AEDs): felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin. Compared to the pharmacokinetics of standard AEDs, these new AEDs have progressed in terms of (a) longer half-lives, permitting once- or twice-daily dosing, (b) greatly reduced potential for drug interactions, thus increasing ease of treatment, and (c) general lack of hepatic enzyme induction, which facilitates polytherapy as well as other aspects of treatment.

Acetates↗
PubMed1988

Gamma-glutamyl transpeptidase alterations in liver and serum induced by haloperidol.

Changes in the activity of the microsomal enzyme gamma-glutamyl transpeptidase (GGT) were examined in liver and serum following subacute and chronic haloperidol administration to rats. Haloperidol increased both serum and liver GGT levels. The enzymatic activity returned to baseline values on the sixth day after withdrawal of the drug. It is concluded that alterations in serum GGT levels may be expected during prolonged treatment of haloperidol, and that these alterations reflect enzyme induction in liver microsomes where the drug is entirely metabolized.

Animals↗
PubMed1975

Nutrition and experimental carcinogenesis: a review.

Restriction of the total diet or the number of calories fed to rats and mice inhibits the formation of tumors in several tissues. Unless animals are fed equivalent levels of food, or attain equivalent body weights, it is difficult to assess the significance of the effect of other nutritional modifications on carcinogenesis. The effects of altering the levels of protein or fat are much less than those seen with dietary restriction. Feeding a protein-free diet is tolerated for a limited period and can alter the metabolism of carcinogens. It may thus affect the tumor incidence induced by one-shot carcinogens. Vitamins have specific effects on the activity of certain carcinogens, the fullest information being available for vitamin A, which has been shown to inhibit or enhance carcinogenesis, and vitamin C, which by reducing sodium nitrite, prevents nitrosation of secondary and tertiary amines occurring in acidic conditions of the stomach. Inorganic substances, such as iodine (thyroid) and copper (liver), may affect the tumor incidence in specific tissues. The metabolic activation of carcinogens is modified by enzyme induction and the administration of antioxidants. The relevance of these results to the induction of cancer in humans is briefly discussed.

Animals↗
PubMed1980

Diurnal variation in the inducibility of luteal 20 alpha-hydroxysteroid dehydrogenase in pregnant rats.

Luteolysis was induced in rats during late pregnancy by fetoplacental removal, and was monitored by the increased activity of luteal 20 alpha-hydroxysteroid dehydrogenase (20 alpha-OHSDH). The extent of enzyme induction over a given length of time varied according to the time of day at which the fetuses and placentae were removed, 11.00 and 21.00 h appearing to give optimal and minimal enzyme activities respectively. The 20 alpha-OHSDH was more readily induced on day 19 than on day 18.

20-Hydroxysteroid Dehydrogenases↗
PubMed1982

Renal cortical accumulation of phenobarbital in rats and rabbits: lack of correlation with induction of renal microsomal monooxygenases.

Subchronic treatment with phenobarbital induces renal cortical microsomal monooxygenase activities (e.g., ethoxycoumarin O-deethylase, benzphetamine N-demethylase and arylhydrocarbon hydroxylase) and cytochrome P-450 content in rabbits but not in rats. The mechanism responsible for this species-specific difference in renal cortical enzyme induction remains unknown, but may be the result of differences in the renal cortical accumulation of phenobarbital by these two species. Rabbit kidneys may be capable of accumulating more phenobarbital than rat kidneys. In the present study, accumulation of phenobarbital by renal cortical slices and the disposition of phenobarbital in vivo were determined. Both rat and rabbit renal cortical accumulation of phenobarbital was partially energy-dependent and inhibited by SKF-525A. Renal cortical accumulation of phenobarbital in rats was also inhibited by piperonyl butoxide. Accumulation of phenobarbital in rabbit renal cortical slices was not greater than that in rat renal cortical slices. Furthermore, rabbit renal cortex did not accumulate more phenobarbital in vivo than rat renal cortex. These results suggest that the different enzyme inducing effects of phenobarbital in rat and rabbit kidneys is not due to quantitative differences in accumulation of phenobarbital in renal cortex.

Animals↗
PubMed1976

The incorporation of 5-iodo-2'-deoxyuridine into the DNA of HeLa cells and the induction of alkaline phosphatase activity.

Inhibition of DNA synthesis during the period of exposure of HeLa cells to 5-iodo-2'-deoxyuridine (IUdR) inhibited the induction of alkaline phosphatase activity. This finding, taken together with previous findings that IUdR did not induce alkaline phosphatase activity in the presence of 2-fold molar excess thymidinemonstrated that IUdR incorporation into DNA is correlated with the increase in alkaline phosphatase activity. With the exception of an interim period described in the text, induction of alkaline phosphatase activity was linearly related to medium concentrations of IUdR of up to at least 3 muM. However, the extent of IUdR substitution in DNA did not appear to be related to the degree of enzyme induction. Alkaline phosphatase activity continued to increase at medium concentrations of IUdR from 1 to 3 muM, while little further substitution of DNA occurred.

Alkaline Phosphatase↗
PubMed1999

Induction of aromatic catabolic activity in Sphingomonas aromaticivorans strain F199.

Enzyme induction studies with Sphingomonas aromaticivorans F199 demonstrated that both toluene and naphthalene induced expression of both naphthalene and toluene catabolic enzymes. However, neither aromatic compound induced expression of all the enzymes required for complete mineralization of either naphthalene or toluene. Activity measurements in combination with gene sequence analyses indicate that growth on either aromatic substrate in the absence of the other is, therefore, sub-optimal and is predicted to lead to the build-up of metabolites due to imbalance in toluene or naphthalene catabolic enzyme activities. Growth on toluene may be further inhibited by the co-expression of two toluene catabolic pathways, as predicted from gene sequence analyses. One of these pathways may potentially result in the formation of a dead-end intermediate, possibly benzaldehyde. In contrast, either p-cresol or benzoate can support high levels of growth. Analyses of promoter region sequences on the F199 aromatic catabolic plasmid, pNL1, suggest that additional regulatory events are modulated through the interaction of BphR with Sigma54 type promoters and through the binding of a regulator upstream of p-cresol catabolic genes and xylM. We hypothesize that the unusual gene clustering in strain F199 is optimized for simultaneous degradation of multiple aromatic compound classes, possibly in response to the heterogeneous composition of aromatic structures in the fossil organic matter present in the deep Atlantic Coastal Plain sediments from which this bacterium was isolated.

Journal Article↗
PubMed1986

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on lipid peroxidation in microsomal systems in vitro.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) when added to suspensions of rat hepatic microsomes in the presence of NADPH has little influence on the peroxidation of microsomal lipids unless the system also contains complexed ferric ion, in which case TCDD stimulates. This stimulation does not appear to require metabolism of the TCDD. Peroxidation was monitored by production of thiobarbiturate-reactive substances (malondialdehyde and dienals), production of conjugated dienes, and disappearance of polyunsaturated fatty acids. Stimulation of lipid peroxidation by TCDD in a mixed lysosome-microsome preparation resulted in significantly decreased 'leakage' of acid phosphatase into the medium, implying an effect on lysosomal membranes. Consideration both of the present results and data in the literature leads to the conclusion that it is premature to attempt to define the relationship between enzyme induction, lipid peroxidation and TCDD lethality.

Acid Phosphatase↗
PubMed1975

Energy wastage in rats given drugs that induce microsomal enzymes.

Metabolic efficiency was studied in rats given drugs known to induce hepatic microsomal enzymes. The presence of an increased metabolic rate was indicated by increases in oxygen consumption under various experimental conditions and by changes in body weight. The latter was not accounted for by increased losses of energy in excreta. The results support the hypothesis that hepatic microsomal enzyme induction can significantly alter the body's metabolic efficiency.

Aminopyrine↗
PubMedDate not supplied

Relation between aryl hydrocarbon hydroxylase inducibility, serum gamma-glutamyltransferase and serum cholesterol in middle-aged smokers and non-smokers.

Aryl hydrocarbon hydroxylase (AHH) inducibility, carbon monoxide in expired air (CO), serum gammaglutamyl-transferase (GGT), and total cholesterol were compared in equal-sized, age-matched samples of healthy middle-aged males born in 1921, 1934-1936, and 1946 attending the ongoing preventive medical population program in Malmö. AHH did not differ in various age - and smoking or non-smoking groups, and there were no correlations between AHH, GGT, and cholesterol. The findings provide evidence against the recent hypothesis that low cholesterol may mediate or reflect a carcinogenic mechanism through a state of general enzyme induction in the body.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

Ethanol inhibition of inducible nitric oxide synthase activity in C6 glioma cells.

Nitric oxide (NO.), a free radical gas, has been implicated in the CNS actions of ethanol. The brain contains several cell types that can produce NO., including neurons and glia. This study examined the effect of acute and chronic ethanol exposure on the activity of the inducible isoform of nitric oxide synthase (iNOS) found in neuroglia. Experiments were performed using intact rat C6 glioma cells, and NO. production was assessed by nitrite accumulation after iNOS induction by coadministration of phorbol 12-myristate 13-acetate (PMA) and lipopolysaccharide (LPS). Ethanol was inhibitory at high concentrations (IC50 approximately 150 mM) when acutely present during the 24-hr period subsequent to initiation of enzyme induction. In contrast, cells exposed to ethanol were inhibited chronically at clinically relevant lower concentrations (IC50 approximately 30 mM with 10 days exposure). Chronic inhibition was both time- and concentration-dependent. Inhibition by ethanol seems to be a consequence of interference with LPS signal transduction. Acutely, ethanol did not affect the ability of PMA to synergize with LPS to induce activity, but it attenuated the ability of LPS to synergize with the PMA. Ten days exposure to 50 mM ethanol decreased the LPS potency by 4-fold in the presence of a maximally activating concentration of PMA, although not significantly changing PMA potency. Inhibition by chronic ethanol exposure was long-lasting, being retained over 24 hr in cells returned to control conditions. Thus, chronic ethanol may downregulate key components needed for iNOS expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1977

Genetic regulation of UDP-glucuronosyltransferase induction by polycyclic aromatic compounds in mice. Co-segregation with aryl hydrocarbon (benzo(alpha)pyrene) hydroxylase induction.

Induction of hepatic 4-methylumbelliferone UDP-glucuronosyltransferase (EC 2.4.1.17) by polycyclic aromatic compounds, such as 3-methylcholanthrene or beta-naphthoflavone, occurs in C57BL/6N, A/J, PL/J, C3HeB/FeJ, and BALB/cJ but not in DBA/2N, AU/SsJ, AKR/J, or RF/J inbred strains of mice. This pattern of five responsive and five nonresponsive mouse strains parallels that of the Ah locus, which controls the induction of aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase (EC 1.14.14.2). Induction of the transferase is maximal in C57BL/6N mice with 200 mg of 3-methylcholanthrene/kg body weight; no induction occurs in nonresponsive DBA/2N mice even at a dose of 400 mg/kg. The rise of inducible transferase activity lags 1 or more days behind the rise of inducible hydroxylase activity and peaks 5 days after a single dose of 3-methylcholanthrene. In offspring from the appropriate backcrosses and intercross between C57BL/6N and DBA/2N parent strains, the genetic expression of 3-methylcholanthrene-inducible transferase activity is inherited as an additive (co-dominant) trait. This expression differs distinctly from that of the inducible hydroxylase activity, which is inherited almost exclusively as a single autosomal dominant trait in these same animals. The more potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin induces the transferase more than 3-fold in C57BL/6N mice and less than 2-fold in DBA/2N mice, whereas the hydroxylase is induced equally (about 8-fold) in both strains. A dose of 3-methylcholanthrene given 3 days after 2,3,7,8-tetrachlorodibenzo-p-dioxin, at a time when hydroxylase induction in both strains is very high, does not enhance the rise in inducible transferase activity seen in C57BL/6N or DBA/2N mice which have received 2,3,7,8-tetrachlorodibenzo-p-dioxin alone. These data indicate that (a) the inducibility of two metabolically coordinated membrane-bound enzyme activities may be regulated by a single genetic locus, and (b) although the hydroxylase can be fully induced in the nonresponsive DBA/2N strain by 2,3,7,8-tetrachlorodibenzo-p-dioxin prior to 3-methylcholanthrene treatment, metabolites of the 3-methylcholanthrene treatment, metabolites of the 3-methylcholanthrene treatment, metabolites of the 3-methylcholanthrene, presumably present in the liver, are incapable of inducing further the transferase activity. The difference in sensitivity between 3-methylcholanthrene and the more potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin for both the hydroxylase and the transferase activities suggests the possibility of a common receptor in regulating both enzyme induction processes.

Age Factors↗
PubMedDate not supplied

[Hepatitis, cholestasis and amineptine (author's transl)].

Eight cases of hepatitis induced by amineptine chlorhydrate, a new tricyclic antidepressant are reported. Jaundice and/or biological changes occurred 16 to 75 days after the onset of treatment and with a total oral dose of 3,8 to 26 grams. Biologically, cholestasis and cytolysis have been observed simultaneously in 4 cases, cholestasis alone in 2 cases, and prevalent cytolysis in 2 others. After withdrawal of amineptine, clinical improvement was achieved within 10 to 21 days, whereas biological changes of hepatic function tests lasted for as long as 3 to 12 weeks. Physiopathology of such disorders is not clear : toxicity, enzyme induction, immunoallergy, may be considered as possible mechanisms.

Adult↗
PubMed1984

Rapid elevation of plasminogen activator activity in rat tissues by prolactin.

Administration of ovine prolactin resulted in a rapid and significant induction of plasminogen activator activity within two hours in the rat adrenal gland, heart, aorta and liver. Prolactin exposure reduced baseline proteolytic activity in lung and skeletal muscle at 6-8 hours following hormonal challenge. This was coincident with a return toward baseline levels in enzyme activity demonstrated in other tissues. Pretreatment with actinomycin D or cycloheximide ameliorated the enzymic induction in the liver and adrenal and partially inhibited the aortic response. These data suggest that prolactin exposure leads to increased proteolytic activity through de novo biosynthesis in a variety of solid organs. In addition, pro-enzyme activation may also occur in vascular tissue.

Animals↗
PubMed1998

Differences in kinetics of induction and reversibility of TCDD-induced changes in cell proliferation and CYP1A1 expression in female Sprague-Dawley rat liver.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent tumor promoter in two-stage initiation-promotion models and induces cell proliferation and development of enzyme-altered hepatic foci. It is believed that increased cell proliferation is a necessary step in carcinogenesis. Therefore, the analysis of the effect of TCDD on cell proliferation in rat liver may aid in the understanding of the mechanism of hepatocarcinogenesis induced by TCDD. The aim of this study was to investigate the time course and reversibility of cell proliferation in non-initiated and diethylnitrosamine-initiated female rats exposed biweekly to a daily averaged dose of 125 ng TCDD/kg/day for up to 60 weeks. In addition we evaluated the suitability of different dose metrics for the evaluation of TCDD-induced changes in cell proliferation and CYP1A1 enzyme induction. Cell proliferation was measured as the incorporation of 5-bromo-2'-deoxyuridine (BrdU) into hepatocytes undergoing replicative DNA synthesis. Mean BrdU labeling indices in TCDD-treated animals were not increased over controls after 14 weeks exposure, but were increased 8- and 2-fold after 30 and 60 weeks' treatment respectively, despite similar liver levels of TCDD at all these times (23-30 p.p.b.). In comparison, CYP1A1 activity, as measured by ethoxyresorufin deethylase activity, was significantly induced at all times points analyzed. Sixteen weeks following cessation of TCDD treatment, labeling indices were still significantly elevated over controls, but after 30 weeks of withdrawal, labeling indices were no different from controls, indicating that TCDD-induced changes in cell proliferation were reversible. Dosimetric analysis indicated that rat liver tissue burden was suitable for prediction of CYP1A1 expression but not cell proliferation and that the area under the curve was unsuitable for prediction of both TCDD-induced changes in CYP1A1 expression and cell proliferation.

Animals↗
PubMed1985

Nucleosidediphosphate-kinase induction by human recombinant IL-2 in mouse NK cells.

The ability of human recombinant IL-2 to induce NDP-kinase in mouse NK cells has been studied. A significant increase in the amount of NDP-kinase was observed when the cells were exposed to IL-2 (100 units/ml) for 3 h at 37 degrees C. The enzyme inducting ability of human recombinant IL-2 was similar to that of native mouse IL-2 in the cells. The enzymatic characteristics [chemical requirements for the phosphoenzyme formation and molecular size of two distinct subunits (18,000 and 20,000 daltons)] of NDP-kinase from IL-2 treated cells were similar to those of the enzymes from EAT cells. The enzyme's biological role in the initiation of cell proliferation by IL-2 has been discussed.

Animals↗