Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation of glutathione (GSH) conjugate in the detoxification of [1-14C]-naphthalene and [naphthyl-14C]-carbaryl was investigated using rat liver homogenate. The mercapturic acid conjugate in rats was also investigated by collection of urine after intraperitoneal injection of 14C substrates. The formation of water-soluble metabolites in vitro from naphthalene was dependent on the amount of glutathione added, but this was not seen in carbaryl metabolism. In vitro, the metabolism of [1-14C]-naphthalene produced 50% GSH conjugates in the incubation mixture, whereas in vivo the metabolism of this compound produced 65% mercapturic acid conjugate in the urine. There was no evidence of GSH or mercapturic acid conjugate in the metabolism of [naphthyl-14C]-carbaryl in vitro and in vivo. This conclusion was made by comparing the nature and chemical characteristics of GSH and mercapturic acid conjugates formed in [1-14C]-naphthalene metabolism. With the aid of the specific enzyme (e.g. beta-glucuronidase and sulfatase) and acid hydrolysis, the water-soluble metabolites of [naphthyl-14C]-carbaryl were tentatively recognized as glucuronide or sulfate conjugated mainly with 5,6-dihydro-5,6-dihydroxycarbaryl or N-hydroxy-methyl carbaryl and their hydrolytic products. This data demonstrated that the substituent group on the naphthalene molecule may affect the significance of GSH conjugation.
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PMID:Glutathione and mercapturic acid conjugations in the metabolism of naphthalene and 1-naphthyl N-methylcarbamate (carbaryl). 12 Feb 42

Since human colorectal tumors are insensitive to most chemotherapeutic agents, there is a need for the discovery of new drugs that would show activity against this disease. In an attempt to better appreciate the relevance of a widely used mouse colon tumor (colon adenocarcinoma Co38) as a screening model for human colorectal tumors, we compared the main phase I and phase II drug-metabolizing enzyme systems in both tumoral and nontumoral colon tissues. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C, 2E1, and 3A), epoxide hydrolase, and glutathione-S-transferases (GST-alpha, -mu, and -pi). The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: total cytochrome P-450, 1-chloro-2,4-dinitrobenzene-GST, selenium-independent glutathione peroxidase, 3,4-dichloronitrobenzene-GST, ethacrynic acid-GST, total glutathione, epoxide hydrolase, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. Results obtained by Western blot showed that mouse colon adenocarcinoma Co38 did not express any of the probed cytochromes P-450, whereas human colorectal tumors expressed only low levels of cytochrome P-450 3A. GST-alpha and GST-pi were detected in all tumoral and nontumoral tissues of both species. The neutral GST-mu was expressed in all murine tissues investigated and was found to be polymorphic in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzyme levels, whereas mouse colon adenocarcinoma Co38 had a lower expression of GST-mu and GST-pi, compared to normal mouse colon. Enzymatic activities for glutathione peroxidase, 3,4-dichloronitrobenzene-GST, and ethacrynic acid-GST confirmed the Western blot results for GST-alpha, GST-mu, and GST-pi, respectively. Total GSH levels were similar between murine and human tumors but were 3-fold higher in human tumors than in peritumoral tissues, whereas they were 7-fold lower in mouse colon tumor Co38, compared to normal mouse colon. Epoxide hydrolase was not expressed in either mouse colon adenocarcinoma Co38 or normal mouse colon tissues, whereas it was expressed in human colon peritumoral and tumoral tissues at similar levels. No significant difference was observed between human tumors and peritumoral tissues for UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. For murine colon tissues, the conjugation pathways (UDP-glucuronosyltransferase and sulfotransferase) were lower in colon adenocarcinoma Co38, whereas the converse was observed for the corresponding hydrolytic enzymes (beta-glucuronidase and sulfatase).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. 142 2

After ip administration of 3-tert-butyl-4-hydroxyanisole (3-BHA) to rats, two previously undocumented metabolites 2-tert-butyl-5-methylthiohydroquinone (TBHQ-5-SMe) and 2-tert-butyl-6-methylthiohydroquinone (TBHQ-6-SMe) were identified in the urine by comparison with the authentic samples by GC/MS. In addition to these metabolites, 3-tert-butyl-4,5-dihydroxyanisole was also detected in the urine hydrolyzed by beta-glucuronidase/sulfatase. Administration of tert-butylhydroquinone (TBHQ), an O-demethylated metabolite of 3-BHA, also resulted in the formation of the S-containing metabolites, TBHQ-5-SMe and TBHQ-6-SMe. After incubation of TBHQ with rat liver microsomes in the presence of glutathione (GSH), two metabolites were isolated and purified by HPLC. The metabolites were identified as 2-tert-butyl-5-(glutathion-S-yl)hydroquinone and 2-tert-butyl-6-(glutathion-S-yl)hydroquinone by 1H- and 13C-NMR spectrometry and by fast atom bombardment-mass spectrometry. The formation of TBHQ-GSH conjugates required NADPH, molecular oxygen, and GSH. Cytochrome P-450 inhibitors such as SKF 525-A and metyrapone markedly inhibited the formation of TBHQ-GSH conjugates in vitro. These results suggest that TBHQ is converted by cytochrome P-450-mediated monooxygenases to a reactive metabolite, 2-tert-butyl-p-benzoquinone (TBQ), which then conjugates with GSH to form TBHQ-GSH conjugates. GSH S-transferase activities do not seem to play a role in GSH conjugation reaction to TBQ because cytosol fraction from rat liver homogenates did not enhance the microsome-mediated production of TBHQ-GSH conjugates.
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PMID:Identification and structure characterization of S-containing metabolites of 3-tert-butyl-4-hydroxyanisole in rat urine and liver microsomes. 168 7

1. Orally administered 3H-benzo[a]pyrene (3H-BaP) was excreted in the bile of White Suckers predominantly as water soluble metabolites some of which were hydrolyzed by arylsulfatase or beta-glucuronidase. 2. Non-hydrolysible polar metabolites comprised a substantial proportion of biliary metabolites. 3. HPLC analysis revealed fluorescent and 3H-labelled peaks which co-eluted with standards of the glucuronide and sulfate conjugates of BaP. 4. The most polar peak co-chromatographed with a double-radiolabelled metabolite produced in vitro with 3H-BaP and 35S-glutathione. 5. Inhibition of epoxide hydrolase in vitro reduced all water soluble metabolites except the glutathione conjugate of BaP. 6. Glutathione conjugation represents a major hepatic detoxication pathway of BaP in White Suckers.
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PMID:The role of glutathione S-transferases in the hepatic metabolism of benzo[a]pyrene in white suckers (Catostomus commersoni) from polluted and reference sites in the Great Lakes. 197 53

The effect of selenium (SeO2) and glutathione (GSH) on the bioaccumulation of mercury (HgCl2) and on the activities of lysosomal enzymes in four species of tropical estuarine lamellibranchs is reported. A definite correlation between mercury levels in the external medium and tissue uptake and physiological behaviour--opening and closing of shell valves, response to mechanical stimulus, mucus secretion, and incidence of bleeding--was evident. In the clams exposed to Hg (range 0.1-5.0 mg l-1), bioaccumulation was dependent on the ambient concentration of Hg. The highest bioaccumulation of Hg occurred during the initial 24 h exposure period. Further exposure of up to 7 days did not increase the body burden of Hg. Of the four bivalve species exposed to 0.1 mg Hg l-1, Perna viridis showed the highest levels of Hg (approximately 47 ppm) followed by Anadara granosa, A. rhombea (approximately 25 ppm) and Meretrix casta (approximately 9 ppm). The uptake of Hg by A. granosa was greatly reduced by GSH, whereas Se enhanced it by 50% when administered in combination with Hg. However, the presence of Hg did not influence the uptake of Se. Exposure to combined GSH and Hg resulted in almost complete inhibition of Hg uptake in all four bivalve species. Prior exposure to GSH, however, did not have the same influence on their uptake of Hg. Nevertheless, exposure of clams to GSH following initial exposure to Hg resulted in complete depuration of accumulated Hg. The activities of lysosomal enzymes--arylsulfatase, acid phosphatase, beta-galactosidase and beta-glucuronidase--varied considerably. Treatment with Hg and GSH, separately and in combination, significantly enhanced the levels of beta-galactosidase (P less than 0.05) and beta-glucuronidase (P less than 0.001) in the digestive gland after 96 h exposure. Although Se increased beta-glucuronidase activity (P less than 0.001), it had no effect on beta-galactosidase. On exposure to Hg + Se the activity of both enzymes decreased, except in P. viridis where it increased by 39%. The results show unequivocally that Se does not offer any protection against the toxic effects of mercury in marine lamellibranchs, whereas in many marine vertebrates it does. GSH, a thiol-rich tripeptide, on the other hand, completely nullifies the toxic effects of Hg, both in vivo and in vitro.
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PMID:Do selenium and glutathione inhibit the toxic effects of mercury in marine lamellibranchs? 323 22

Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917 +/- 444 mg (range, 300-1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-alpha, -mu, and -pi) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), beta-glucuronidase (beta G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-alpha, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P < 0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-mu, GST-pi, GSH, and beta G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P < 0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.
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PMID:Influence of tumor size on the main drug-metabolizing enzyme systems in mouse colon adenocarcinoma Co38. 792 60

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance has been mostly studied in vitro. In an attempt to better understand BCNU resistance in the in vivo situation, we compared the principal drug-metabolizing enzyme systems in two L1210 leukemia lines, one sensitive and one resistant to BCNU (L1210/BCNU), passaged in vivo in mice. The following enzymes were assayed by immunoblotting: cytochromes P-450 (1A1/1A2, 2B1/2B2, 2C8-10, 2E1, 3A), epoxide hydrolase (EH) and glutathione S-transferase (GST-alpha, -mu and -pi). The following enzymes and cofactors were assayed fluorometrically or spectrophotometrically: 1-chloro-2-4 dinitrobenzene-GST (CDNB-GST), total glutathione (GSH), UDP-glucuronosyltransferase, beta-glucuronidase, sulfatase and sulfotransferase. Results showed that cytochrome P-450 1A1/1A2 was the only isoenzyme detected in both L1210 and L1210/BCNU. CDNB-GST activity was significantly higher in L1210/BCNU compared with L1210. The isoenzyme GST-alpha was more abundant in L1210/BCNU compared with L1210, whereas GST-pi was expressed less in the BCNU-resistant leukemia line. GST-mu was not detected in either L1210 leukemia lines. GSH levels were similar in the two L1210 lines. No significant difference was observed between the two leukemia lines for the conjugative enzymes UDP-glucuronosyltransferase and sulfotransferase, whereas their corresponding hydrolytic enzymes beta-glucuronidase and sulfatase were about two-fold lower in the BCNU-resistant leukemia line. Epoxide hydrolase was 1.3-fold higher in L1210/BCNU compared with L1210 and this level was about three-fold higher than in mouse liver. In conclusion, these studies showed the presence of cytochrome P-450 1A1/1A2 in the two L1210 leukemia lines studied, and indicated noteworthy differences between the two leukemia lines for many enzyme systems such as GST, beta-glucuronidase, sulfatase and epoxide hydrolase. These data are of importance to better understand the mechanisms of drug resistance to nitrosoureas in vivo.
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PMID:Principal drug-metabolizing enzyme systems in L1210 leukemia sensitive or resistant to BCNU in vivo. 796 9

Since drug-metabolizing enzymes may influence the toxic response of tissues or organs to drugs, we studied their expression in human and colon tumor tissues, in an attempt to find new targets for chemotherapy and also to explain the intrinsic drug-insensitivity of most colon tumors to anticancer drugs. In the present work, we compared human colorectal tumors and peritumoral tissues to a mouse colorectal tumor (Co38) and normal murine colon with regard to their main drug-metabolizing enzyme systems. We investigated cytochromes P-450 (1A1/1A2, 2B1/B2, 2C, 2E1, 3A) and epoxide hydrolase (EH) by immunoblotting. Total glutathione (GSH) and the activities of the following enzymes: total GST, selenium-independent glutathione peroxidase (GPX), 1,2-dichloro-4-nitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), UDP-glucuronosyltransferase 1 (UDPGT), beta-glucuronidase (beta G), sulfotransferase (ST) and sulfatase (S) were investigated by fluorometric and spectrophotometric assays. Results obtained by immunoblotting showed that mouse colon tumor Co38 did not express any of the probed cytochromes P-450, whereas human tumors showed the presence of cytochrome P-450 3A. EH was not expressed in either mouse colon tumor Co38 or normal mouse colon, whereas it was expressed in human peritumoral and tumoral colon tissues at similar levels. GPX and EA-GST were detected in all tumoral and non tumoral tissues of both species. DCNB-GST was expressed in all murine tissues investigated, but was not found in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzymes levels, whereas mouse colon tumor Co38 had a lower expression of DCNB-GST and EA-GST compared to normal mouse colon. No significant difference was observed between human tumors and peritumoral tissues for total GST, UDPGT1, beta G, ST and S activities. For murine colon tissues, the conjugation pathways (total GST, UDPGT1 and ST) were lower in Co38, whereas the opposite was observed for the hydrolytic enzymes (beta G and S). In conclusion, despite similarities between human and murine colon tumors, mouse colon tumor Co38 appears different from human colon tumors for many drug-metabolizing enzyme systems. These interspecies differences may have implications with regard to drug screening methodologies and preclinical evaluation of candidate anticancer drugs useful in the chemotherapy of human colorectal tumors.
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PMID:[Screening of principal enzymes involved in the metabolism of anticancer drugs in human and murine colonic tumors]. 817 93

In an attempt to better understand breast tumors sensitivity or resistance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S-transferases (GST-alpha, -mu, and -pi); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean +/- SD, 399 +/- 362 nmol/min/mg) than in corresponding peritumoral tissues (86 +/- 67). The GST isoenzymes GST-mu and GST-pi (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-mu and GST-pi levels were significantly correlated with GST activity. GST-alpha was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 +/- 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 +/- 12). Epoxide hydrolase was expressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 +/- 0.2 nmol/h/mg) than in peritumoral tissues (0.5 +/- 1), whereas the opposite was observed for the hydrolytic enzyme beta-glucuronidase, which was 6-fold higher in tumors (736 +/- 1392 nmol/h/mg) compared to peritumoral tissues (125 +/- 75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase (1 +/- 2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 +/- 15 nmol/h/mg) than in peritumoral tissues (6 +/- 2). In conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-mu, GST-pi, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and beta-glucuronidase). These noteworthy differences between tumoral and peritumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.
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PMID:Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. 833 60

Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L. Cavalieri et al. (1997) Proc. Natl Acad. Sci. USA, 94, 10937-10942]. Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes. The quinones formed can be detoxified by reaction with glutathione (GSH) or can covalently bind to DNA. To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-hydroxyestradiol (4-OHE2) by intraperitoneal injection. The highest level of conjugates was observed 1 h after treatment, and almost none was detected after 24 h. Dose-response studies indicated conjugate formation after treatment with 0.5 micromol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 micromol/100 g body weight. GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by high-performance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry. Treatment of tissue homogenates with beta-glucuronidase/sulfatase at 37 degrees C for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels. Similar enhancement was observed by just incubating the tissue at 37 degrees C for 6 h. Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.
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PMID:Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer. 1123 91


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