Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of trans-stilbene oxide (TSO) induction on the microsome-catalyzed binding of polycyclic aromatic hydrocarbon metabolites to DNA was investigated using two rodent species (Sprague-Dawley rat and C57BL/6N or NMRI Swiss mouse) and 2 different binding substrates (benzo[a]anthracene). It was determined that TSO exerts 2 separate effects on polycyclic aromatic hydrocarbons - it increases the rate of oxidation at the K-region of the molecule due to its induction of specific monooxygenases, and it increases the rate of deactivation of epoxide intermediates by induction of microsomal epoxide hydrolase activity. The importance of these individual effects were determined by inducing monooxygenase activity with BP, altering region specificity and inducing epoxide hydrolase (EH) activity with TSO, assessing the combined inductive effects of TSO and BP, inhibiting EH with 1,1,1-trichloropropene oxide, or increasing its activity by the addition of pure enzyme. This study shows that these effects are similar for both substrates examined, and that the effect of TSO on the binding to DNA of highly carcinogenic bay-region diol-epoxides is multi-faceted, due to its multiple inductive effects.
Carcinogenesis 1981
PMID:Modulation of the covalent binding of aryl hydrocarbon metabolites to DNA in vitro after treatment of rats and mice with trans-stilbene oxide. 627 11

Using brain, lung and liver microsomes as the enzyme source in in vitro assays, benzo[a]pyrene (B[a]P) metabolism was studied in fetuses and dams of mice (C57B1/6) and rats (WAG). Separation and quantitation of B[a]P metabolites were performed by h.p.l.c. Microsomal preparations were tested for cytochrome P-450 dependent O-dealkylation of 7-ethoxycoumarin and epoxide hydrolase activities. Another parameter measured included the conjugation of 1-chloro-2,4 dinitrobenzene to glutathione by cytosolic glutathione-S-transferase activity. The induction of B[a]P metabolism was studied after treatment of animals with 5,6-benzoflavone (BF). Mixed function oxygenase, epoxide hydrolase and glutathione-S-transferase activities were transplacentally inducible after dams were treated with BF. Metabolic activation of B[a]P by fetal brain microsomes was lower in both species than that by fetal lung and liver microsomes, but it was higher in fetuses than in adults. All metabolites of B[a]P increased after BF treatment; the production of 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (7,8-dihydrodiol B[a]P) was higher in brain microsomes from BF-treated rats than that in mice. In stimulated rats, the formation of 7,8-dihydrodiol B[a]P by fetal brain microsomes were higher than that by fetal lung microsomes, whereas in mice, the opposite was observed. These data suggest that initiation could occur in utero, and partially explain the species-specific differences in susceptibility to transplacental tumorigenesis by polycyclic aromatic hydrocarbons by differences in biotransformation in the target organ.
Carcinogenesis 1981
PMID:Metabolism of benzo[a]pyrene by brain microsomes of fetal and adult rats and mice. Induction by 5,6 benzoflavone, comparison with liver and lung microsomal activities. 627 16

A benzo[a]pyrene (B[a]P) hydroxylase activity and epoxide hydrolase (EH) activity have been found in rat liver nucleoli obtained from untreated (C) and 3-methylcholanthrene (3-MC) pretreated rats. A comparison of the enzyme activities was made in rat nuclei and nucleoli. Light and electron microscopic observations of nucleolar preparations did not reveal significant contamination either by intact nuclei or by nuclear membranes, and glucose 6-phosphatase, a marker of microsomal activity, was not detected in our nucleolar preparations. NADPH cytochrome c-reductase could be measured in C and 3-MC nuclei and very low but detectable activity was found in the nucleoli. Nucleolar preparations revealed significant hydroxylating activity, which was inducible by 3-MC in nuclei but not in nucleoli. The presence of EH in nucleoli was demonstrated with phenanthrene 9,10-oxide and B[a]P 4,5-oxide, but the nucleolar activities were lower than those obtained using intact nuclei. The addition of 1,1,1-trichloropropene 2,3-oxide completely inhibited EH activity. Furthermore the presence of covalently-bound metabolites of B[a]P formed in isolated nucleoli was demonstrated by cytofluoromicroscopy.
Carcinogenesis 1981
PMID:Presence of benzo[a]pyrene metabolizing activities in isolated rat liver nucleoli. 627 39

Results of various studies have shown that male Swiss Webster mice are more susceptible to toxic effects of vinylidene chloride (VDC) than are females of the same mouse strain, females and males of the C57BL mouse strain, Chinese hamsters and rats. The main targets of toxicity are kidney and liver. The kidney of male Swiss Webster mice is the only organ where VDC unambiguously induces tumours. In the present study we have investigated the ability of NADPH-foritifed postmitochondrial supernatant fractions (S-9 mix) of kidney and liver from susceptible and nonsusceptible animals to activate VDC to a bacterial mutagen. The following sequence of activating potencies was observed: mouse liver (both strains and sexes) and Chinese hamster liver greater than rat liver greater than human liver greater than Chinese hamster kidney greater than kidney from male mice of both strains greater than kidney from rats and female mice. The last two preparations only occasionally showed weak activation of VDC. Addition of purified microsomal epoxide hydrolase to S-9 mix did not affect the mutagenicity of VDC; addition of glutathione reduced the mutagenicity up to 50%. Pretreatment of animals (male rats, male and female Swiss Webster mice) with VDC did not potentiate the ability of the subcellular preparations to activate this compound. In fact, in some cases, a weaker activation was observed. Following this treatment, microsomal 7-ethoxy-coumarin O-dealkylase was decreased in mouse kidney and in rat liver. The enzyme was not affected in mouse liver and was not measurable in rat kidney. Microsomal epoxide hydrolase activity (with styrene 7,8-oxide as substrate) was not affected in mouse liver and rat kidney. In the kidney of male mice treated with a high concentration of VDC, epoxide hydrolase activity was decreased initially, but after longer treatment, in some cases a weak increase above control was noticed. A stronger increase in activity of epoxide hydrolase was observed in the rat liver and the kidney of female mice. Cytosolic glutathione transferase activity (with 2,4-dinitrochlorobenzene as substrate) was not affected by the VDC treatment in the liver of male mice, but was decreased in the kidney of male mice, and was elevated in the kidney and liver of rats and of female mice. The different effects of VDC on this enzyme may be one of the reasons for the differences in susceptibility towards the toxic and carcinogenic actions of this compound in different species, strains and sexes.
Carcinogenesis 1983 Aug
PMID:Vinylidene chloride: changes in drug-metabolizing enzymes, mutagenicity and relation to its targets for carcinogenesis. 634 25

A highly sensitive assay for the epoxide hydrolase activity associated with the preneoplastic antigen (PNA) has been developed based on the synthesis of cis-stilbene oxide labeled with tritium at approximately 15 Ci/mmol. This assay allows the detection of elevated epoxide hydrolase activity in the serum of humans and rodents as well as in the culture medium bathing isolated hepatocytes. The integrity of the enzymatic assay was confirmed in rodents by precipitating the serum PNA activity using an antibody raised against the rat microsomal epoxide hydrolase. Methodology for the detection of PNA in serum will facilitate evaluation of this antigen as a marker for hepatic neoplasia in man and in experimental animals.
Carcinogenesis 1984 Nov
PMID:A methodology for the analysis of the preneoplastic antigen. 648 72

Hepatocarcinogens have been shown to cause marked elevation of hepatic microsomal epoxide hydrolyase activity in the rat at short intervals after administration. The present studies were designed to characterize 2-acetylaminofluorene (AAF) mediated epoxide hydrolase elevation and to investigate the relationship between epoxide hydrolase increases, AAF metabolism, and hepatocarcinogenicity. Oral or i.p. administration of AAF to F-344 rats produced log-linear dose-response curves for epoxide hydrolase elevation, measured with either benzo[a]pyrene-4,5-oxide or styrene oxide substrate. Following a single dose of AAF (35 mg/kg), epoxide hydrolase activity was maximally increased (560% of control) within 48 h, and the activity declined slowly, with a half-life of 17.5 days. Co-treatment with actinomycin D effectively blocked the AAF dependent increase in epoxide hydrolase, suggesting that de novo protein synthesis is associated with the increase in enzyme activity. Dose-response curves for epoxide hydrolase induction by AAF, N-hydroxy-2-acetylaminofluorene (N-OH-AAF), and 2-aminofluorene were compared, and the potencies for increasing epoxide hydrolase activity reflected the relative hepatocarcinogenic potentials of these agents. In mice, which are resistant to the hepatocarcinogenic action of AAF and deficient in AAF-N-hydroxylase activity, AAF caused no significant increase in hepatic microsomal epoxide hydrolase activity. Similarly, in Cotton rats and guinea pigs, which are lacking in ability to form the sulfate conjugate of N-OH-AAF, neither i.p. nor dietary administration of AAF elicited increases in epoxide hydrolase activity at doses which were maximally effective in F-344 rats. These results support the hypothesis that the ability of compounds to increase epoxide hydrolase activity is related to their carcinogenic potency. Furthermore, the results suggest that increases in epoxide hydrolase activity are associated with metabolism of AAF to the putative proximate carcinogen N-OH-AAF, and the subsequent conversion of this compound to the N-O-sulfate conjugate.
Carcinogenesis 1984 Jan
PMID:Elevation of hepatic microsomal epoxide hydrolase activity by 2-acetylaminofluorene: strain and species differences. 669 83

Biotransformation of lipophilic xenobiotics may lead to formation of reactive intermediates which can give rise to irreversible toxic events such as carcinogenesis, mutagenesis, teratogenesis, and tissue necrosis. In recent years considerable attention has been paid to the problem of testing for these effects. Short-term mutagenicity tests have been shown to have value for predicting the occurrence of delayed toxic effects in mammals following administration of indirectly acting harmful xenobiotics. In any test system the capacity to bioactivate the compound under test is a necessary prerequisite, and in most short-term test assays this is provided for by adding a metabolic activation system generally consisting of the 9,000 g supernatant fraction of a rat liver homogenate supplied with cofactors. The fruitfly Drosophila melanogaster constitutes an organism well-suited for mutagenicity testing, and it was shown that a number of precarcinogens evoke mutagenic effects in this species. Thus Drosophila is apparently able to metabolize xenobiotics to reactive intermediates, which in turn induce mutagenicity. However, knowledge about the presence and characteristics of the xenobiotic-metabolizing enzymes involved is lacking. Since knowledge of these enzymes contributes to the evaluation and interpretation of observed mutagenic events, this paper described studies concerning some important xenobiotic-metabolizing enzymes of Drosophila. Files were homogenized and subcellular fractions were investigated with respect to enzymatic activities. It was possible to demonstrate cytochrome P-450 and some related mixed-function oxidase activities. Cytochrome b5, epoxide hydrolase, and glutathione S-transferase are also present, while preliminary experiments suggest the presence of UDP-glucosyltransferase and phosphotransferase activities. The enzymes which have been found are discussed with respect to their similarities with rat liver enzymes and their relevance for mutagenicity testing with Drosophila melanogaster.
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PMID:Biotransformation of xenobiotics in Drosophila melanogaster and its relevance for mutagenicity testing. 678 78

A rapid and sensitive indirect enzyme-linked immunosorbent assay (ELISA) was developed for microsomal epoxide hydrolase of rat liver. The assay, which is easily and readily performed, is significantly more sensitive than most enzymatic epoxide hydrolase assays routinely used and electroimmunoassays previously developed. The limit of sensitivity of the ELISA is between 2-5 ng of microsomal epoxide hydrolase. Using the ELISA microsomal epoxide hydrolases of mouse and rat liver were shown to be antigenically very similar, while microsomal epoxide hydrolases of guinea pig, monkey and human liver are antigenically distinct from those of rat and mouse. The ELISA developed here is capable of detecting microsomal epoxide hydrolase of rat and mouse liver even when significant enzymatic activity is lost. These results indicate that the antigenic sites recognized by the antibodies used are distinct from the catalytic site of the epoxide hydrolase. Approximately 1.9% of rat microsomal protein was quantified as microsomal epoxide hydrolase by the ELISA. Low levels of microsomal epoxide hydrolase were also detected in rat liver cytosol (approximately 0.02% of the cytosolic protein) demonstrating that microsomal epoxide hydrolase is not totally membrane bound or that an immunologically related protein occurs in the cytosol of normal rat liver. The ELISA developed here will be valuable in investigating further the role of microsomal epoxide hydrolase.
Carcinogenesis 1982
PMID:Rapid and sensitive enzyme-linked immunosorbent assay for the microsomal epoxide hydrolase. 681 36

A number of drug-metabolizing systems were measured in hyperplastic noduli from the livers of rats receiving 2-acetyl-aminofluorene in their diet and compared with corresponding activities in control liver. The level of microsomal cytochrome P-450 is reduced 54% in the nodular tissue, while 5 activities catalyzed by the cytochrome P-450 system (i.e., aminopyrine N-demethylase, benzo[a]pyrene monooxygenase, ethoxyresorufin O-deethylase, ethoxycoumarin O-deethylase, and 2-acetylaminofluorene N-hydroxylase) are all present at levels corresponding to 5-44% of the control levels. The pattern of 2-acetylaminofluorene metabolites formed by nodule microsomes also differs from the pattern observed with control microsomes. Microsomal epoxide hydrolase is increased 415%, cytosolic glutathione S-transferases 203-576%, microsomal UDP-glucuronyltransferase activity about 200%, and cytosolic DT-diaphorase 1210% in the nodules. The same changes are seen in nodules of different sizes and in individual nodules of the same size. Finally, of all of these changes only the full increase in epoxide hydrolase can be seen after 1-3 weeks of exposure to 2-acetylaminofluorene.
Carcinogenesis 1983
PMID:Characterization of drug-metabolizing systems in hyperplastic nodules from the livers of rats receiving 2-acetylaminofluorene in their diet. 685 Sep 90

Benzo[f]quinoline and benzo[h]quinoline are widespread environmental pollutants which have been found to be mutagenic. The metabolism of benzo[f]quinoline and benzo[h]quinoline was investigated using a liver homogenate from Aroclor-pretreated rats. The metabolites of benzo[f]quinoline which were identified were 7,8-dihydroxy-7,8-dihydrobenzo[f]quinoline, 9,10-dihydroxy-9,10-dihydrobenzo[f]quinoline, 7-hydroxybenzo[f]quinoline, and benzo[f]quinoline-N-oxide. Metabolism studies on benzo[f]quinoline performed in the presence of the epoxide hydratase inhibitor, 3,3,3-trichloropropylene oxide, demonstrated that the formation of both of these dihydrodiols can be inhibited. The major metabolites of benzo[h]quinoline were identified as 5,6-dihydroxy-5,6-dihydrobenzo[h]quinoline and 7,8-dihydroxy-7,8-dihydrobenzo[h]quinoline. Benzo[h]quinoline-N-oxide was not detected as a metabolite. In the presence of an epoxide hydratase inhibitor, the major metabolites of benzo[h]quinoline were 5,6-epoxybenzo[h]quinoline and 7-hydroxybenzo[h]quinoline. The difference in the metabolism to N-oxides observed between benzo[h]quinoline and benzo[f]quinoline is consistent with previous observations in which sterically hindered aromatic ring nitrogen compounds such as benzo[h]quinoline are more resistant to N-oxide formation. The nitrogen atom of these aza-arenes with its lone pair of electrons has a significant influence on sites at which dihydrodiols are formed. The data suggest that the aromatic ring nitrogen of these azaphenanthrenes has an effect similar to that of a methyl substituent in directing their metabolic oxidation.
Carcinogenesis 1983 Sep
PMID:Identification of the metabolites of benzo[f]quinoline and benzo[h]quinoline formed by rat liver homogenate. 688 36


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