Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secondary cultures of hamster embryo cells exposed to 0.5 nmol [G-3H]7,12-dimethylbenz(a)anthracene (DMBA) per ml medium metabolized more than 90% of the DMBA within 48 hr. Samples of medium were extracted with chloroform, methanol, and water. The chloroform phases contained about one-third of the DMBA metabolites; the major chloroform-extractable metabolite was 8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz(a)anthracene. Beta-glucuronidase treatment of the aqueous methanol-soluble metabolites converted almost one-half of them to chloroform-soluble metabolites, of which more than 80% were identified as phenolic derivatives of DMBA. Similar metabolite profiles were obtained by treating the medium with beta-glucuronidase before chloroform extraction. Separation of the methyl group-hydroxylated derivatives of DMBA from the phenolic derivatives was accomplished by high-pressure liquid chromatography. Small amounts of hydroxymethyl derivatives were detected only in the chloroform-extractable material, whereas DMBA phenols were the major component of the beta-glucuronidase-released mateirla. These results indicate that the major pathway of DMBA metabolism in hamster embryo cells is oxidation of the aromatic rings and not oxidation of the methyl groups.
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PMID:Formation of glucuronic acid conjugates of 7,12-dimethylbenz(a)anthracene phenols in 7,12-dimethylbenz(a)anthracene-treated hamster embryo cell cultures. 9 31

Two monoclonal antibodies (10C10 and 4D5) have been developed from the spleen cells of Balb/c mice immunized with 6-aminobenzo[a]pyrene covalently coupled to bovine serum albumin. These antibodies have been used in an immunoassay for the detection of benzo[a]pyrene and its metabolites in mouse urine. The antibodies were characterized in terms of sensitivity and specificity by competitive enzyme-linked immunosorbent assay (ELISA). With both antibodies, 50% inhibition of antibody binding is at 4 pmol of BP. The antibodies also cross-react with a number of BP metabolites as well as with several other polycyclic aromatic hydrocarbons (PAHs) including pyrene, 1-aminopyrene, and 7,12-dimethylbenz[a]anthracene but with different sensitivities. These results suggest that this assay will detect multiple PAH metabolites in urine. To test the assay on biological samples, mice were treated with [3H]BP, and urine was collected and digested with beta-glucuronidase and aryl sulfatase. Several methods were used to isolate BP and its metabolites from the urine, including ethyl acetate extraction, Sep-pak C18 cartridge chromatography, XAD2 resin chromatography, and immunoaffinity chromatography with antibody 4D5. Analysis of the urine extracts with antibody 4D5 gave 50% inhibition at 12-15 pmol of metabolites. Thus, quantitation of metabolites in this sample by competitive ELISA against a standard curve of BP would have underestimated actual metabolite levels by about 70%. This assay will be applied to the analysis of urines from individuals with environmental or occupational exposure. Since humans are usually exposed to BP in complex mixtures of PAHs, multiple metabolites may be present in the urine, making absolute quantitation difficult. This assay should thus serve as a general indicator of exposure to this class of chemicals.
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PMID:Immunologic methods for the detection of benzo[a]pyrene metabolites in urine. 213 77

The exposure of murine skin to potent chemical carcinogens induced distinctive effects on the distribution of epidermal Langerhans cells (LC). Our previous finding that weekly applications of 7,12-dimethylbenz[a]anthracene deplete the numbers of adenosine triphosphatase (ATPase)-positive LC was extended to show that LC are also depleted on Ia and beta-glucuronidase staining. In contrast, application of the tobacco-derived carcinogen, benzo[a]pyrene (BP), caused a significant increase in Ia-positive LC density within 2 weeks and elevated levels were maintained for up to 6 months with continuous treatment. The tobacco-derived cocarcinogenic agent, catechol, also enhanced the numbers of epidermal LC. The LC in carcinogen treated epidermis were morphologically abnormal; after BP and catechol treatment LC appeared smaller with shorter dendrites, whereas in DMBA treated epidermis LC were enlarged with elongated dendrites. Application of the contact sensitizing agent, dinitrofluorobenzene, to skin treated with BP induced hyporesponsiveness rather than contact sensitivity upon subsequent antigen challenge. Hence, the function of the large number of morphologically altered LC in BP treated skin was impaired. We conclude that carcinogen-induced alterations of LC are associated with impaired immunocompetence, although different carcinogens probably operate via different mechanisms to induce such phenomena.
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PMID:Differential effects of benzo[a]pyrene and dimethylbenz[a]-anthracene on Langerhans cell distribution and contact sensitization in murine epidermis. 249 54

Using as a criterion the inhibition of serum beta-glucuronidase activity, dietary calcium D-glucarate is shown to serve as an efficient slow-release source in vivo of D-glucaro-1,4-lactone, the potent endogenous inhibitor of this enzyme. Using the 7,12-dimethylbenz[a]anthracene model of mammary tumor induction in rats it is shown for the first time that feeding the rats calcium D-glucarate-supplemented diet after treatment with the carcinogen, inhibits tumor development by over 70%. Supportive evidence is presented for the theory that calcium D-glucarate inhibits or delays the promotion phase of mammary carcinogenesis by lowering endogenous levels of estradiol and precursors of 17-ketosteroids. Therefore, dietary glucarate can be used to lower blood and tissue levels of beta-glucuronidase, and in turn of those carcinogens and promoting agents which are excreted, at least in part, as glucuronide conjugates.
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PMID:Dietary glucarate as anti-promoter of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis. 309 Dec 83

Some effects of two isomeric polycyclic aromatic hydrocarbons, anthracene and phenanthrene, on the fine structure and cytochemistry of digestive cells in the marine mussel Mytilus edulis have been investigated. The cytochemical results show that increasing concentrations of anthracene and phenanthrene have different effects on the acid labilization time for latent beta-glucuronidase which is used to measure the stability of lysosomal membranes. At the ultrastructural level the limiting membranes of secondary lysosomes appear multilayered, with discontinuities and overlaps. Under the conditions of the experiment, only phenanthrene produces changes in this configuration. Both macroautophagic and microautophagic processes occur in the control and hydrocarbon treatments, and complementary data from other studies indicate that autophagic processes are enhanced by polycyclic aromatic hydrocarbons. Phenanthrene also causes proliferation of the smooth endoplasmic reticulum in the digestive cells, although cytochemical measurements of smooth endoplasmic reticulum-associated NADPH-ferrihemoprotein reductase show that anthracene stimulates activity over a greater range of concentrations than phenanthrene. The different effects of the two isomers is taken as evidence that the molecular configuration of the compound determines its reactivity with membranes and its subsequent effect on the physiology of the cells.
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PMID:Effects of polycyclic aromatic hydrocarbons on molluscan lysosomes and endoplasmic reticulum. 311 40

Rat mammary tumours induced by 7,12-dimethylbenz[a]anthracene can undergo repeated growth and regression during successive pregnancies. In a 10-day period after birth about half of the tumours regressed 50% or more. The concentrations of the lysosomal enzymes increased in regressing mammary tumours to the following multiples of the initial values: beta-glucuronidase, 7.7; beta-galactosidase, 3.9; cathepsin, 2.9; acid ribonuclease, 2.1; arylsulphatase A, 1.5; acid phosphatase, 1.4. In contrast, several non-lysosomal enzymes failed to increase. Activities in the post-partum uterus increased to the following multiples of the initial values: beta-glucuronidase, 5.8; cathepsin, 5.5; acid ribonuclease, 4.3; beta-galactosidase, 2.2; acid phosphatase, 1.8. Arylsulphatase A in the post-partum uterus decreased significantly, suggesting a non-lysosomal distribution or a special function related to pregnancy. No other significant changes were observed in the lysosomal or non-lysosomal enzymes in the hormone-independent liver or hormone-dependent normal mammary gland. The ratio of free to bound arylsulphatase A and acid ribonuclease decreased slightly 1-3 days after birth because of problems in homogenizing the tumours. At days 4-8, however, there was a dramatic increase in the ratio of the free to bound activities. The results can be explained in terms of the lysosomal theory of intracellular digestion.
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PMID:Lysosomal enzyme changes in growing and regressing mammary tumours. 576 57

This in vitro study examined the ability of various dietary fiber components to bind 7,12-dimethylbenz[a]anthracene (DMBA), a hydrocarbon carcinogen known to contaminate food. Bile salt solutions of DMBA were incubated with individual fiber materials under various conditions, and the degree of binding was assessed. Binding of DMBA from simple bile salt solution was greatest with delipidated bran greater than acid lignin greater than alpha-cellulose greater than unprocessed bran. Binding to acid lignin was slowly reversible, was constant within the pH range 4-8, and appeared independent of a bile salt-fiber interaction. Acid lignin bound DMBA from a mixed lipid-bile salt solution significantly, but less effectively than from pure bile salt solutions. DMBA biliary metabolites from Sprague-Dawley rats were bound less extensively to all the fiber materials than was the parent hydrocarbon, but following hydrolysis of the metabolites by beta-glucuronidase binding was significantly increased. These results indicate that there is considerable potential for dietary fiber to interact with DMBA and its metabolites in the lumen of the gastrointestinal tract, possibly influencing hydrocarbon carcinogen bioavailability.
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PMID:In vitro interaction of 7,12-dimethylbenz[a]anthracene and its biliary metabolites with dietary fiber. 630 23

Sprague-Dawley rats bearing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were treated with either of two aromatic alkylating agents, aniline mustard or melphalan, alone or combined with ovariectomy. Both drugs were applied once a week for 8 weeks. Eight-four percent of the tumors responded to ovariectomy, 38% regressing completely and 46% regressing partially. Aniline mustard, though virtually ineffective as a single agent, appeared synergistic with ovariectomy: a 100% regression rate (72% complete, 28% partial) was observed for this combination. Treatment with melphalan was as effective as ovariectomy, but the combination of melphalan with ovariectomy was no more effective than either treatment alone. The end product of aniline mustard metabolism, p-hydroxyaniline mustard O-glucuronide, may be more extensively activated by beta-glucuronidase in hormonally regressing than in growing or stationary tumors. Intratumoral levels of beta-glucoronidase occurring in DMBA-induced tumors 4 days after ovariectomy were found to be similar to those in the aniline mustard-sensitive mouse plasma cell tumor ADJ/PC6. It remains to be more extensively studied whether an effect of endocrine treatment on tumor beta-glucuronidase levels, and possibly on intracellular distribution of enzyme, could be used therapeutically. An effectively scheduled cytostatic treatment (with a drug conjugate such as that formed metabolically from aniline mustard) in conjunction with ovariectomy might be effective in the treatment of hormone-responsive breast cancer.
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PMID:Enhanced cytostatic effectiveness of aniline mustard against 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors during regression in response to ovariectomy. 678 69

Field studies suggest that recent epizootics of hepatic neoplasms in some feral fish populations are associated with polycyclic aromatic hydrocarbon (PAH) exposure, but attempts to induce liver tumors in these species under laboratory conditions have been unsuccessful. Several studies have shown hepatic neoplasma to be inducible in laboratory fish species following PAH exposure at the free-swimming life stage. However, neither the susceptibility of the fish embryonic life stage to tumor induction by PAHs nor the potential of these carcinogens to induce oncogenic point mutations analogous to those reported in feral fish hepatic tumors have been clearly established. To address this, rainbow trout embryos were exposed by passive water uptake to 7,12-dimethylbenz[a]anthracene (DMBA), a potent model PAH in many mammalian tumor protocols. DMBA was rapidly absorbed by trout eggs and metabolized. The major non-polar metabolites identified were 12-hydroxymethyl-7-methylbenz[a]anthracene and 3,4-dihydroxy-3,4-dihydro-DMBA, whereas approximately 25% of the water soluble metabolites were identified as glucuronides by beta-glucuronidase treatment. Embryonic DNA adduction increased with time of DMBA exposure (2.2 +/- 0.3 pmol DMBA-equivalents/mg DNA at 24 h). Liver tumor incidence nine months after DMBA treatment was found to increase with DMBA concentration and exposure period (3.8% at 1 p.p.m./2 h; 23% at 5 p.p.m./2 h; 85% at 5 p.p.m./24 h). Stomach adenomas and nephroblastomas also were observed at low incidence in the DMBA-treated trout. Among 11 hepatic tumors examined, nine carried Ki-ras alleles with activating point mutations in codon 12 (4/11 GGA-->AGA; 4/11 GGA-->GTA) or codon 61 (1/11 CAG-->CTG). This spectrum differs substantially from those reported for DMBA-initiated mouse skin papillomas or hepatic tumors. These results may have important environmental implications because they suggest that even a brief exposure to PAHs during a sensitive stage of development may adversely affect some fish populations. They also indicate considerable variation in DMBA ras gene mutations among species and target organs.
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PMID:Carcinogenicity, metabolism and Ki-ras proto-oncogene activation by 7,12-dimethylbenz[a]anthracene in rainbow trout embryos. 847 26

Consumption of fossil fuels has increased indoor and outdoor concentrations of polycyclic aromatic hydrocarbons (PAHs) and nitrogen dioxide (NO2). To study the combined effect of PAH administration and NO2 exposure on mutagenicity of urine from animals we injected 400 mg/kg body wt i.p. one of five kinds of PAH (pyrene, fluoranthene, fluorene, anthracene and chrysene) into ICR mice, Wistar rats, Syrian golden hamsters or Hartley guinea pigs after exposure to 20 p.p.m. NO2 gas for 24 h and then exposed the animals to NO2 gas for an additional 24 h. During the latter 24 h we collected the urine and assayed its mutagenicity with the Ames Salmonella strains after treatment with beta-glucuronidase and arylsulfatase and extraction with dichloromethane. The urine from mice treated with both PAH and NO2 showed high mutagenicity for Salmonella typhimurium strains TA98 and TA100, whereas the urine from mice treated with PAH and air showed almost no mutagenic activity. The mutagenicity was decreased in nitroreductase- and acetyltransferase-deficient strains TA98NR and TA98/1,8-DNP6 respectively. Treatment with a mixture of 20% of each of the five kinds of PAH and NO2 augmented the urinary mutagenicity of mice 1.5-fold. The urine from hamsters treated with pyrene or fluoranthene and NO2 was also highly mutagenic, but that from rats or guinea pigs was not very mutagenic. The mutagenicity was also decreased in strains TA98NR and TA98/1,8-DNP6. These results suggest that the urine contains nitro compounds and that the nitration of PAHs occurs in the body of animals under exposure to NO2 gas. Actually, the nitrated metabolites of pyrene, 1-nitro-6/8-hydroxypyrene and 1-nitro-3-hydroxypyrene, were detected in the urine from mice treated with pyrene under exposure to NO2 gas. To elucidate the mechanism of in vivo nitration, NO2 (20 p.p.m.) was bubbled through 50 mM Tris-HCl buffer (pH 7.4) or dichloromethane solution containing pyrene or 1-hydroxypyrene (10 microg/ml). Pyrene was not nitrated by NO2 in either aqueous or organic solutions. However, 1-hydroxypyrene was changed to nitrohydroxypyrenes by NO2 in the Tris-HCl buffer, but not in the organic solution. Ascorbic acid, alpha-tocopherol, glutathione oleic acid and hemoglobin were found to inhibit the nitration of 1-hydroxypyrene in aqueous solution. The urinary mutagenicity of mice treated with both pyrene and NO2 was also decreased by oral administration of ascorbic acid and alpha-tocopherol. These results suggest that 1-hydroxypyrene is nitrated by an ionic reaction in the animal body after hydroxylation of pyrene in the liver.
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PMID:In vivo formation of mutagens by intraperitoneal administration of polycyclic aromatic hydrocarbons in animals during exposure to nitrogen dioxide. 870 53


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