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PubMed1976

[Enzyme induction in Streptomyces hydrogenans, VI. Studies on the induction of 20beta-hydroxysteroid dehydrogenase, using immunological methods].

Antiserum against crystallized 20beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans was used for various immunodiffusion and immunoprecipitation tests to show an increase of the de novo synthesis of 20beta-hydroxysteroid dehydrogenase by Streptomyces hydrogenans after cultivation of the cells in the presence of 11beta,21-dihydroxy-4,17(20)-pregnadien-3-one. Half lives of mRNA for 20beta-hydroxysteroid dehydrogenase in induced cells and of total mRNA in non-induced cells were calculated to be 126 s and 66 s, respectively. In vivo, 20beta-hydroxysteroid dehydrogenase appears to consist of four equal subunits. The monomers, molecular weight of 27 300, show a high tendency to form dimers and tetramers in the absence of dissociating agents. The aggregation is completely reversible in the presence of increasing concentrations of sodium dodecylsulfate.

Animals↗
PubMed1983

Rat hepatic microsomal enzyme induction by pretreatment with toxaphene and toxaphene fractions.

The levels of hepatic microsomal induction caused by toxaphene were determined. Young Sprague-Dawley rats (70 g) were administered toxaphene (ip injection, daily for 5 d) at 0, 5, 25, and 100 mg/kg. All doses caused increases in liver/body weight ratio, cytochrome P-450 level, aminopyrine demethylation, and aldrin epoxidation. The aldrin epoxidase activity increased almost 700% at the 100-mg/kg dose. Toxaphene was separated into nonpolar (S-A) and polar (S-B) fractions and administered as before at 25 mg/kg. All treatments caused significant increases in cytochrome P-450, aminopyrine demethylation, and aldrin epoxidation. A comparison of the treatments, however, did not reveal any significant differences between the treatments.

Animals↗
PubMed2001

Differential effects of two lots of aroclor 1254 on enzyme induction, thyroid hormones, and oxidative stress.

Aroclor 1254 is a commercial mixture of polychlorinated biphenyls (PCBs), which is defined as being 54% chlorine by weight. However, the congener composition varies from lot to lot. Two lots which have been used in toxicity studies, 124-191 and 6024 (AccuStandard), were analyzed for their congener composition. Lot 6024 has approximately 10 times the dioxin toxic equivalents (TEQ) of lot 124-191. The purpose of this study was to determine if the difference in the TEQ of the two lots explains the different in vivo responses seen on a weight basis. Male Long-Evans rats (70 days old) were treated orally with a single dose of 0-1,000 mg/kg of each lot. Hepatic ethoxy-, methoxy-, and pentoxyresorufin O-deethylase (EROD, MROD, and PROD, respectively) activities as well as serum thyroxine (T(4)) concentrations and measures of oxidative stress were determined 4 days after treatment. Results, on a weight basis, indicate that lot 6024 led to a greater induction of EROD, MROD, and PROD but not total T(4) reduction. The differences in TEQ between the lots explained the differential induction of EROD and MROD but did not account for the induction of PROD nor decreases in T(4). PROD induction is not due to dioxin-like congeners, whereas the decrease in serum T(4) levels may involve multiple mechanisms. Effects on the antioxidants ascorbic acid and uric acid were seen only at the highest mass dose for both lots and were not explained by the difference in TEQ. These results illustrate that the differences in the TEQ explain the differences in the strict dioxin-like effects (EROD, MROD induction), but the non-dioxin-like congeners cause other effects that are not associated with the aryl hydrocarbon receptor (e.g., PROD). In addition, supra-additive effects also occur in the mixture (T(4), oxidative stress). Thus, current results demonstrate that overall toxicity cannot be predicted on the basis of the TEQ values. It is also critical that the lot number is reported in studies conducted with Aroclor 1254 because the congener composition and therefore the effects observed can be very different.

Administration, Oral↗
PubMed1983

Correlation between biochemical tests, parameters of drug elimination and hepatic enzyme induction in chronic liver diseases.

The biochemical liver function tests form an integral part of diagnostic practice in hepatology. In this study the parameters suited for the estimation of drug elimination and of the induced state of the liver, thus the excretion of D-glucaric acid, of menthol glucuronide and the parameters of antipyrine and sulphadimidine kinetics were correlated with the results of biochemical laboratory tests in patients with chronic liver disease. The aim was to establish universally valid quantitative correlations between the above results. Multiple relationships were revealed, but generally valid correlations for the group of liver diseases occurred only in special relationships (serum albumin level and antipyrine T1/2; serum bilirubin level and sulphadimidine T1/2). The results have been evaluated from the methodological aspect to work out an appropriate dosage regime in liver diseases.

Adult↗
PubMed1980

Enzyme induction by o-xylene inhalation.

Inhalation of 4500 mg o-xylene by rats was found to produce adaptational and pathologic changes in the liver by the end of the 1st week, reflected in an increase in relative liver weight, shortening of the hexobarbital sleeping time, an increase in the concentration of cytochrome P-450, with a decrease in the activities of aniline hydroxylase and of aminopyrine N-demethylase. Six weeks after the start of inhalations all the changes in the liver and in the mixed function oxydase system (MFO) were of an adaptational pattern characterized by an increase in relative liver weight as well as in cytochrome P-450 and b5 concentrations, a shortening of the hexobarbital sleeping time and an increase in the activity of aniline hydroxylase and of aminopyrine N-demethylase.

Adaptation, Physiological↗
PubMed1997

Hepatic enzyme induction and mutagenicity of airborne particulate matter from Santiago, Chile in the nourished and malnourished rat.

1. Respirable, airborne particles in the ambient air in downtown Santiago, Chile, have been characterized for the seasonal variation in total polycyclic aromatic hydrocarbon content, 13 of which have been identified including the mutagens (benzo(a)pyrene, dibenzo(a,h)anthracene, benzo(a)anthracene, benzo(b)fluoranthene and indeno(1,2,3, c,d)pyrene amongst others. 2. Organic extracts derived from these particles were administered to both the nourished and malnourished rat and resulted in modulation of the hepatic mixed function oxidase system including induction of NADPH-cytochrome P450 reductase, cytochrome P4501A as determined by Western blot analysis and the associated ethoxyresorufin O-deethylase and aryl hydrocarbon hydroxylase activities. 3. The cytochrome P4504A1-dependent 12-hydroxylation of lauric acid was induced in the malnourished state, but this activity was significantly inhibited by treatment of the animals with particle extracts in both nutritional states. 4. The particle extracts contained both direct and indirect-acting mutagens in the Ames test, and depending on the relative complement of both, resulted in either increased or decreased mutagenicity in the presence of S9 activation systems derived from both nourished and malnourished animals. 5. These results are discussed in the context of the interindividual risk assessment of airborne, particulate matter to man.

Air Pollutants↗
PubMed1993

Enzyme induction of the early chick embryo by airborne particulate extracts.

The induction by airborne particulate extracts of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase (ECOD) in early chick embryos was studied to determine whether or not lethality by the extracts was related to the induction. The optimal pH values for AHH and ECOD were 7.1 and 6.9, respectively, after administering the extracts to early embryos. The AHH inducing capacity was significantly increased 4 h after injection of the extracts, then the value gradually increased. The ECOD inducing ability was similar to that of AHH, although to a lesser extent. Among fractions from the extracts, the neutral fraction was responsible for most of the AHH inducing activity. Two neutral subfractions (N2 and N3), consisting mostly of polycyclic aromatic hydrocarbons (PAH) and their derivatives, had the highest inducing activity. A dose-response relationship was observed between the amounts of the N2 and induction of AHH and ECOD in 8-day-old embryos. When the N2 was administered at different stages of development (days 5-9), the values of induced AHH and ECOD activities increased along with the days of development. Extracts of the smaller airborne particulates (< 1.1 and 1.1-2.0 microns cut-off diameters) had stronger AHH and ECOD inducing abilities than those of the larger, since the former contained high levels of PAH and their derivatives. These results suggested that PAH and their derivatives in the airborne particulates induced AHH and ECOD activities in the early chick embryo. The relationship between the extent of AHH and ECOD inducing activities and that of embryolethality caused by extracts of airborne particulates was not well established.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1993

Lack of stereoselectivity in rat liver peroxisomal enzyme induction by optically active phenoxyacetic acids.

To ascertain if there is stereoselectivity in peroxisomal proliferation induced by chiral peroxisome proliferators, induction by stereoisomers of 2-methyl-4'-chlorophenoxyacetic acid and 2-methyl-2-(2'-4'-dichlorophenoxy)acetic acid were studied in rat in vivo and in vitro with isolated rat hepatocytes. No significant differences in the inducing potencies of the stereoisomers of the above two phenoxyacetic acid derivatives were found for cyanide-insensitive fatty acyl-CoA oxidizing system, fatty acyl-CoA oxidase, carnitine acetyltransferase or carnitine palmitoyltransferase. There was also no significant difference in the degree of hepatomegaly or lipid-lowering effect between the isomers. The findings with cultured rat hepatocytes agreed with those of the studies in vivo.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Xenobiotic metabolism and enzyme induction in isolated rat intestinal microsomes.

Intestinal microsomes were isolated from rats pretreated with 3-methylcholanthrene (MC), phenobarbital (PB), and pregnenolone-16alpha-carbonitrile (PCN). The metabolism of benzo[a]pyrene (BP), 7-ethoxyresorufin, 7-ethoxycoumarin, and biphenyl were examined. MC induces a 30-fold increase in BP metabolism. With control microsomes, BP metabolism is inhibited by metyrapone, SKF 525-A, and antimycin A, but is stimulated 4.5-fold by rotenone. With microsomes from MC-treated rats, BP metabolism is inhibited by metyrapone, SKF 525-A, antimycin A, and rotenone. MC pretreatment increases 7-ethoxyresorufin de-ethylase by almost 20-fold and ethoxycoumarin de-ethylase by almost 18 fold. PB pretreatment produces less than a 2-fold increase in both de-ethylases. PCN pretreatment inhibits 7-ethoxyresorufin and 7-ethoxycoumarin de-ethylases. In rats fasted for 2 days, neither de-ethylase could be detected in intestinal microsomes. Biphenyl 2- and 4-hydroxylase activities were induced less than 4-fold by MC or PB pretreatment.

Animals↗
PubMedDate not supplied

Metabolism of 8-hydroxymethylbenz[a]anthracene by rat liver microsomes. Stereochemistry of dihydrodiol metabolites and the effect of enzyme induction.

Metabolism of the carcinogen 8-hydroxymethylbenz[a]anthracene (8-HOCH2-BA) with liver microsomes from 3-methylcholanthrene-treated rats resulted in 12 identifiable metabolites. Trans-1,2-, 3,4-5,6-, 8,9-, and 10,11-dihydrodiols are among the identified metabolites. The major enantiomers of the trans-dihydrodiols have 1R,2R, 3R,4R, 5R,6R, 8S,9S, and 10R,11R absolute configurations, respectively. Metabolites formed by liver microsomes from untreated as well as 3-methylcholanthrene-, phenobarbital-, and polychlorinated biphenyl-treated immature male Sprague-Dawley rats were quantified by using specifically tritium-labeled [3H-CH2]8-HOCH2-BA as the substrate. The identification of an 8,9-dihydrodiol as a metabolite of 8-HOCH2-BA indicates that a hydroxymethyl substituent does not prevent the enzymatic oxidation at the hydroxymethyl-substituted 8,9-double bond of 8-HOCH2-BA. This is the first example of such a dihydrodiol found from the metabolism of a hydroxymethyl-substituted polycyclic aromatic hydrocarbon by rat liver microsomes.

Animals↗
PubMed2002

Microsomal enzyme induction and clinical aggravation of porphyria: the evaluation of human urinary 6beta-hydroxycortisol/cortisol ratio as the index of hepatic CYP3A4 activity.

The clinical aspect of porphyria has been investigated, and it is well known that porphyrinogens such as estrogens and alcohol or other inducers of P450 isoenzymes exacerbate the porphyric state. However, there can be a delay in diagnosing porphyria and a difficulty in selecting safe medicine for it even today. A 21-year-old woman developed epilepsy, disturbance of mental state, and spastic tetraparesis during the convalescent period after acute viral encephalitis. She was diagnosed with porphyria after the fifth hospitalization. In the course of modifying her anticonvulsant regimen, the authors examined the 6beta-hydroxycortisol/cortisol ratio (6beta-OHF/F) in her urine, which can be the index of hepatic CYP3A4 activity, with electrospray ionization/mass spectrometry/mass spectrometry (ESI/MS/MS). Generalized and partial complex seizures, other neurological signs and symptoms, and laboratory data were improved after modification of her anticonvulsant regimen. This is the first report of evaluating the urinary 6beta-hydroxycortisol/cortisol ratio in a case of porphyria.

Adult↗
PubMed1984

Mutagen sensitivity, smoking habits and enzyme induction in healthy middle-aged men.

Unscheduled DNA synthesis (UDS) (excision-repair) of N-acetoxy-2-acetylaminofluorene (NA-AAF) damage to the DNA of human lymphocytes and levels of 3H-labeled NA-AAF bound to the DNA (carcinogen binding) of lymphocytes after 18 hr of culturing were measured in a consecutive subsample of healthy middle-aged males attending a multiphasic health screening program at the Department of Preventive Medicine in Malmö during 3 weeks in November-December 1981, and compared relative to their smoking habits, body weight, serum cholesterol, and gamma-glutamyltransferase levels as well as aryl hydrocarbon hydroxylase inducibility. This study group numbered 66 males and was uniform in sex, age, and investigation time. No case of significant arterial hypertension was present. The UDS and carcinogen binding results showed no correlation with the other factors measured, with the exception of smoking which was strongly (P less than 0.01) associated with increasing levels of both the UDS and carcinogen binding values. It is concluded that under ordinary circumstances smoking may represent the most important exogenous factor which may modulate risk to cardiovascular disease and cancer by influencing individual mutagen sensitivity.

Acetoxyacetylaminofluorene↗
PubMed1991

Structure elucidation of acid reaction products of indole-3-carbinol: detection in vivo and enzyme induction in vitro.

The potency of indole-3-carbinol (I3C) to form condensation products under acidic aqueous conditions was studied. After identifying a known dimer, 3,3'-diindolylmethane (DIM), we elucidated the structures of two trimers also found in acid reaction mixtures: 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]tri-indole (CTI), and 2,3-bis[3-indolylmethyl] indole (BII). The formation of these indole oligomers was shown to be pH dependent. The highest amounts of DIM and BII were formed in aqueous solutions having a pH value ranging from 4 to 5. No CTI could be detected at pH values above 4.5. In rats that received an oral dose of I3C we could detect DIM and BII in gastric contents, stomach tissue, small intestine and liver. No CTI could be detected in vivo after oral exposure to I3C. In in vitro experiments, using rat hepatocytes, the cytochrome P-450IA1 apoprotein level, 7-ethoxyresorufin O-deethylation activity (EROD) and DT-diaphorase activity (DTD) were markedly enhanced by DIM and CTI as well as BII.

Animals↗
PubMed1990

Promotion of altered hepatic foci development in rat liver, cytochrome P450 enzyme induction and inhibition of cell-cell communication by DDT and some structurally related organohalogen pesticides.

The organochlorine pesticide 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and four structural analogues (bromopropylate, chlorobenzilate, dicofol and fenarimol) were investigated for their ability to inhibit gap junctional intercellular communication both in the Chinese hamster V79 metabolic co-operation assay and in the scrape-loading/dye-transfer assay in WB-F344 rat liver epithelial cells. The pesticides were also studied for their ability to enhance the development of gamma-glutamyltranspeptidase-positive altered hepatic foci and induce cytochrome P450 monooxygenase isoenzymes in nitrosamine-initiated male Sprague-Dawley rats. The in vitro studies showed all organohalogens except fenarimol to be potent inhibitors of cell-cell communication in both test systems used. Concomitant results were recorded in the in vivo study. Thus, all potent inhibitors of intercellular communication were found to enhance significantly foci development and fenarimol was again without any significant effect. All pesticides studied were shown to be potent inducers of the phenobarbital-inducible cytochrome P450b isoenzyme and to cause hepatomegaly. Thus, no strict correlation between cytochrome P450b induction/liver growth and tumour promotion-related effects in vivo and in vitro was apparent for these organohalogen pesticides in the present study.

Animals↗
PubMed1995

Early biochemical markers of effects: enzyme induction, oncogene activation and markers of oxidative damage.

Experimental carcinogenicity studies focus on identification of single carcinogens. Humans, however, appear exposed to a variety of low doses of carcinogens. Furthermore, few chemical entities are carcinogenic or toxic per se, but require metabolic activation to form ultimate carcinogens or toxins. In contrast to experimental animals, humans show considerable difference in genetic properties. In that situation it is particularly important to estimate individual capability for metabolic activation. To an increasing extent, activation includes formation of toxic oxygen metabolites. Particular targets for activated species are DNA and lipids; in particular low-density lipoproteins (LDL). Modifications of DNA are important for initiating the multistep process of carcinogenesis, in particular if oncogenes are activated or if tumor supressor genes are inactivated. Such DNA modification can be identical regardless of the reactive specimens being a xenobiotic or an oxygen species. Modification of LDL can start the process of atherosclerosis by transforming macrophages into foam cells, deposited as fatty streaks in the arterial wall. Biomarkers for activation capacity of xenobiotics include the use of prototype substrates and molecular techniques to determine genetic polymorphisms. Oxidative DNA modification can be measured from urinary excretion of oxidatively modified deoxynucleosides, particularly guanosine. Future efforts have to include individual measurements in order to improve the 'resolution' of molecular epidemiological approaches.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1975

Characterization of the growth of Pseudomonas putida LP on lipoate and its analogues: transport, oxidation, sulphur source, and enzyme induction.

Pseudomonas putida LP, which grows on lipoate, NH4NO3 and mineral salts, converts most of the organic substrate to bisnor-lipoate (1,2-dithiolane-3-propanoic acid) and acetyl-CoA. D-, L-, or DL-lipoate serve equally well as carbon and sulphur sources. There was no growth on or bacterial oxidation of the chemically synthesized bisnor- or tetranor-(1,2-dithiolane-3-carboxylic acid) chain-shortened analogues, but these, as well as lipoate, could supply the sulphur needed for growth when acetate was provided as the sole source of carbon. The uptake of lipoate by the bacterium is very slow and non-inducible, while the uptake of acetate is faster than octanoate. The oxidation of octanoate is more rapid and extensive than that of lipoate. Levels of acyl-CoA synthetase are not affected by the source of carbon, but activities of isocitrate lyase and malate synthase are higher when the cells are grown in acetate, octanoate or lipoate and lower when glucose is the carbon source. The glyoxylate cycle is induced to facilitate utilization of acetyl-CoA derived from lipoate, which is also degraded to water-soluble catabolites that yield the much smaller amount of sulphur required for growth.

Acetates↗
PubMed1992

Enzyme induction and receptor-binding affinity of steroidal 20-carboxamides in rat hepatoma tissue culture cells.

The steroidal 20-carboxamides [(20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene] recently have been shown to possess anti-inflammatory activity in animal models of inflammation. These N-substituted methyl, ethyl, n-propyl, and benzyl derivatives also exhibited suppressive effects on plasma corticosterone and thymus function. Generally, the (20R)-hydroxy-20-carboxamides were more potent than the corresponding (20S)-epimers. In continuing investigations on the glucocorticoid effects of these compounds, we have studied their ability to induce tyrosine aminotransferase (TAT), inhibit uptake of [3H]thymidine into DNA, and complete with [3H] dexamethasone for binding to the hepatoma tissue culture glucocorticoid receptor. Results indicated that the N-substituted methyl, ethyl, and n-propyl derivatives were full glucocorticoid agonists in the three measurements. Receptor binding affinities of the N-substituted carboxamides correlated well with their ability to induce TAT activity and to inhibit thymocyte proliferation. Structure-activity relationships indicated that the larger the N-substituent, the weaker the agonist activity in this system, and 20R isomers exhibited higher glucocorticoid agonist activity than the corresponding 20S isomers. This investigation is part of our effort to elucidate structure-activity relationships of steroidal carboxamides synthesized on the basis of the antedrug concept.

Animals↗
PubMed1984

Correlations between polychlorinated biphenyl immunotoxicity, the aromatic hydrocarbon locus, and liver microsomal enzyme induction in C57BL/6 and DBA/2 mice.

The suppression of the antibody response by polychlorinated biphenyls (PCB) in mice is dependent on the planarity of the PCB molecule and on the expression of the aromatic hydrocarbon (Ah) receptor. In this study, the hypothesis that this form of immunotoxicity is a consequence of the activation of the Ah gene complex and that other compounds which are Ah receptor ligands would also be immunotoxic was tested. 2,2',4,4'-Tetrachlorobiphenyl (TCB), 2,3,3',4,4',5-hexachlorobiphenyl (HCB), phenobarbital (PB), or beta-naphthoflavone (BNF) was given ip to either C57BL/6 (B6,Ahb/Ahb) or DBA/2 (D2, Ahd/Ahd) mice 2 days before immunization with sheep erythrocytes. Organ weights, histopathology, hemagglutinating antibody titers, and the splenic direct antibody plaque-forming cell (PFC) response were evaluated on Day 5. Hepatic aryl hydrocarbon hydroxylase (AHH) induction by these compounds and by 2,2',5,5'-TCB and 3,3',4,4'-TCB was measured as an indicator of Ah receptor binding and subsequent activation of the Ah gene complex by methylcholanthrene-type inducers, while aminopyrine N-demethylase (APND) was measured as an indicator of PB-type induction. 2,2',4,4'-TCB and PB had no effects on the immune parameters of either strain but induced APND activity in both strains. 2,2',5,5'-TCB slightly induced APND activity in B6 mice. 2,3,3',4,4',5-HCB caused a 70% suppression of PFC per spleen, decreased the serum antibody titer, elevated cytochrome P-450 levels (193%), induced both APND (165%) and AHH (217%) activity in B6 mice, but it induced only APND (156%) activity in D2 mice. 3,3',4,4'-TCB elevated cytochrome P-450 levels (210%) and induced both APND (129%) and AHH (321%) activities in B6 mice but only increased APND activities (115%) in D2 mice. BNF elevated cytochrome P-450 (144%), caused a 49% suppression in PFC per spleen, and induced both APND (156%) and AHH (248%) activities but only in B6 mice. These results support the hypothesis that the immunotoxicity caused by halogenated and polycyclic aromatic hydrocarbons is a consequence of activation of the Ah gene complex and suggests that this toxic effect can be initiated by any Ah receptor ligand.

Aminopyrine N-Demethylase↗