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

---

Query: EC:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Cutaneous UDP-glucuronosyltransferase activity (E.C.2.4.1.17) was demonstrated in rat- and hairless mouse-skin microsomes using 1-naphthol as substrate. 2. Addition of the detergent Brij 35 increased the activity by approximately twofold in both species. 3. Inhibitor studies demonstrated that under the assay conditions used any UDP-glucuronic acid pyrophosphatase or beta-glucuronidase present did not interfere with the conjugation reaction. 4. Substrate inhibition was observed in hairless mouse-skin preparations and biphasic response to increasing naphthol concentration was seen in rat-skin microsomes. 5. The apparent Km values were considerably lower than those reported for liver. The sp. activity (per mg microsomal protein) in unactivated rat-skin microsomes was about 50% of that reported in unactivated rat-liver microsomes. 6. Pretreatment with 3-methylcholanthrene resulted in a small increase in cutaneous UDP-glucuronosyltransferase activities in both species.
...
PMID:UDP-glucuronosyltransferase activity in rat-and hairless mouse skin-microsomes. 681 5

7-Ethyl-10-[4-(piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a potent anticancer agent for lung and gynecological cancers, is metabolized in vivo to the active compound, 7-ethyl-10-hydroxycamptothecin (SN-38), which is subsequently conjugated to SN-38-glucuronide by UDP-glucuronosyltransferase (UDP-GT). Three purified aglycons of natural glucuronides, baicalein, luteolin and glycyrrhetic acid, inhibited UDP-GT activity towards SN-38 as a substrate. The inhibitory potencies of these aglycons toward UDP-GT were similar to that of 1-naphthol. Based on these results, together with our previous finding that the corresponding glucuronides used in the present study strongly inhibited beta-glucuronidase in gut flora, we propose that materials in Kampo (Japanese herbal) medicines containing these aglycons of natural glucuronides could be used in vivo to decrease the enterohepatic circulation of SN-38 and other drugs.
...
PMID:Inhibition of UDP-glucuronosyltransferase by aglycons of natural glucuronides in kampo medicines using SN-38 as a substrate. 749 19

The glucuronidation of the AT1 nonpeptide angiotensin II receptor antagonist, SR 47436 (BMS 186295), was investigated in hepatic microsomes prepared from various species, i.e., Sprague-Dawley rat, Cynomolgus monkey and Caucasian humans. The drug was found to undergo N-glucuronidation on the tetrazole moiety as confirmed by its hydrolysis by beta-glucuronidase, its associated radioactivity when UDP-[U-14C]glucuronic acid was used as substrate and by different techniques such as high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. Glucuronide formation was optimal at pH 5.0 along with a "0.2 mg of Brij 58 per mg of protein" ratio, regardless of the investigated species. Cynomolgus monkey microsomes glucuronidated SR 47436 (BMS 186295) to the greatest extent, with a relative catalytic efficiency 11.0- and 2.6-fold higher than that observed in rat and human, respectively. SR 47436 (BMS 186295) glucuronidation followed Michaelis-Menten kinetics. Bilirubin:UDP-glucuronosyltransferase isoform was not involved, inasmuch as bilirubin did not affect its glucuronidation, 7,7,7-triphenylheptanoic acid was a noncompetitive inhibitor and glucuronidation was only decreased 2-fold in Gunn rats. SR 47436 (BMS 186295) glucuronidation was enhanced markedly after treatment of rats with dexamethasone (Vmax/Km = 71.5 vs. 2.6 in untreated animals). Among the drugs used which undergo phenolic, carboxylic acid, alcohol or tertiary amine glucuronidation, only monodigitoxigenin-monodigitoxoside, flurbiprofen, naproxen, testosterone and estrone inhibited SR 47436 (BMS 186295) glucoronidation in a noncompetitive manner. These data suggest that SR 47436 (BMS 186295) was glucuronidated by a highly dexamethasone-inducible UDP-glucuronosyltransferase isoform(s), different from that involved in the glucuronidation of monodigitoxigenin-monodigitoxoside.
...
PMID:In vitro N-glucuronidation of SB 47436 (BMS 186295), a new AT1 nonpeptide angiotensin II receptor antagonist, by rat, monkey and human hepatic microsomal fractions. 796 61

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.
...
PMID:Principal drug-metabolizing enzyme systems in L1210 leukemia sensitive or resistant to BCNU in vivo. 796 9

A rapid and sensitive radioassay for measuring UDP-glucuronosyltransferase activities (EC 2.4.1.17) toward the major endogenous substrates hyodeoxycholic and hyocholic acids, bilirubin, estriol, androsterone, and testosterone has been developed. In this assay, 14C-labeled glucuronides are formed from the enzyme-catalyzed reaction of 14C-labeled UDP-glucuronic acid with the unlabeled aglycones. Following incubation, the 14C-labeled glucuronides are separated under acidic conditions from the unreacted 14C-labeled UDP-glucuronic acid by a single extraction with ethyl acetate. The recovery of glucuronides into ethyl acetate was greater than 90%, whereas the carryover of unreacted UDP-glucuronic acid into the organic phase was approximately 0.2%. The reaction products extracted into ethyl acetate were characterized by their mobilities in thin-layer chromatography and identified as glucuronides by their sensitivity to hydrolysis with beta-glucuronidase and inhibition of hydrolysis by the specific beta-glucuronidase inhibitor D-saccharic acid-1,4-lactone. The optimal conditions of enzyme reactions with the individual aglycones have been defined with human liver microsomes as enzyme source. For all aglycones investigated, 10-30 micrograms of microsomal protein are sufficient for enzyme estimation. The assay is applicable to biochemical studies of UDP-glucuronosyltransferases, as well as to measurement of these enzyme activities from small amounts of clinical liver specimens.
...
PMID:Radioassay of UDP-glucuronosyltransferase activities toward endogenous substrates using labeled UDP-glucuronic acid and an organic solvent extraction procedure. 808 74

The glucuronidation of the food-borne heterocyclic amine 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) was investigated using hepatic microsomes from several species. PhIP-glucuronic acid conjugates were formed in an NADPH-free system using microsomes from rabbit, dog, guinea pig, and human. Rat, hamster, and mouse microsomes were incapable of directly producing PhIP-glucuronides. The PhIP-glucuronide generated with human microsomes could be resolved by reverse-phase HPLC from that produced with rabbit microsomes. In addition, the human PhIP-glucuronide was susceptible to enzymatic hydrolysis by beta-glucuronidase, whereas the rabbit PhIP-glucuronide did not undergo beta-glucuronidase catalyzed hydrolysis. Fast atom bombardment mass spectrometry of both glucuronides revealed the presence of ions with m/z 401 (M+H+). Rabbit PhIP-glucuronide had a lambda max of 316 nm, similar to that of the parent PhIP. By contrast, a spectral shift in UV absorbance was observed for the human PhIP-glucuronide, which had a lambda max of 305 nm. 1H-NMR spectroscopy and nuclear Overhauser enhancements established that rabbit PhIP-glucuronide was conjugated at the exocyclic amine nitrogen, whereas human PhIP-glucuronide was conjugated at the N3 imidazole ring nitrogen. Km values for PhIP were 0.2-0.3 mM in both species; however, rabbit microsomes exhibited a 22-fold higher Vmax. Collectively, these studies indicate that human and rabbit liver microsomes form structurally different glucuronides of PhIP and suggest the involvement of multiple isoforms of UDP-glucuronosyltransferase. Further, these data suggest that in certain species, including humans, the direct conjugation of PhIP with glucuronic acid may represent a primary route of PhIP metabolism and detoxication.
...
PMID:The direct glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) by human and rabbit liver microsomes. 811 24

To better understand drug and carcinogen metabolism pathways in head and neck squamous cell carcinoma we assayed the principal drug- and carcinogen-metabolizing enzyme systems in both tumors and their corresponding adjacent non-tumoral tissues. Cytochromes P450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase and glutathione S-transferases (GST-alpha, GST-mu, GST-pi) were assayed by immunoblotting. GST activity, total glutathione, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase and sulfatase, were determined by spectral assays. Results showed the absence of all probed cytochromes P450 in tumors and non-tumoral tissues, including P450 1A1/1A2 known to be involved in tobacco-related carcinogenesis. No statistical difference was noted between tumors and adjacent non-tumoral tissues for most enzymes studied (GST-alpha, GST-mu, GST-pi, GST activity, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase and sulfatase). However, total glutathione concentrations were significantly higher (P < 0.05) in tumors (47 +/- 20 nmol/mg protein) than in non-tumoral tissues (19 +/- 9). On the contrary, epoxide hydrolase was significantly less expressed in tumors (18 +/- 9 micrograms/mg protein) compared to corresponding non-tumoral tissues (37 +/- 9). These data provide new information concerning human head and neck cancer biology that could possibly have clinical implications.
...
PMID:Principal xenobiotic-metabolizing enzyme systems in human head and neck squamous cell carcinoma. 833 Mar 40

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.
...
PMID:Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. 833 60

To better understand the importance of drug-metabolizing enzymes in carcinogenesis and anticancer drug sensitivity of human non-small cell lung cancer, we studied the main drug-metabolizing enzyme systems in both lung tumors and their corresponding nontumoral lung tissues in 12 patients. The following enzymes were assayed by Western blot analysis: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); epoxide hydrolase; and glutathione S-transferase isoenzymes (GST-alpha, -mu, and -pi). The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: glutathione S-transferase (GST); total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the presence of cytochrome P-450 1A1/1A2 in both tumoral and nontumoral tissues. P-450 1A1/1A2 levels were 3-fold lower in tumors compared to corresponding nontumoral tissues (P < 0.05). None of the other probed cytochromes P-450 were detected in either tumoral or nontumoral lung tissues. For the glutathione system, no significant difference between tumoral and nontumoral tissues was observed (GST activity, glutathione content, GST-alpha, -mu, and -pi). A positive linear correlation was observed between GST activity and GST-alpha or GST-pi. No significant difference was observed for the glucuronide and the sulfate pathways and their corresponding hydrolytic enzymes. Epoxide hydrolase was significantly decreased in tumors compared to nontumoral lung tissues (P < 0.05). In conclusion, these results showed differences between non-small cell lung tumors and nontumoral tissues for cytochrome P-450 1A1/1A2 and epoxide hydrolase. These differences between tumors and peritumoral tissues with regard to these drug-metabolizing enzymes could reflect differences occurring after malignant transformation and may play a role in drug sensitivity to anticancer drugs.
...
PMID:Main drug- and carcinogen-metabolizing enzyme systems in human non-small cell lung cancer and peritumoral tissues. 840 35

Non-Hodgkin's lymphomas (NHL) are one of the most chemosensitive human malignancies. Complete response (CR) is often achieved, but many patients relapse and a second CR is difficult to obtain because of the development of chemoresistance. In an attempt to better understand the biology and the chemosensitivity of these lymphoid tumors, we assessed the main drug-metabolizing enzyme systems in normal lymphocytes, chemosensitive NHL and chemoresistant NHL. Cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase and glutathione S-transferases (GST-alpha, -mu, -pi) were assayed by immunoblotting. UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, sulfatase, GST activity, and glutathione (GSH) content, were determined by spectral assays. Results showed the absence of all probed cytochromes P-450 in normal lymphocytes and NHL cells tested. GST activity was significantly lower in chemoresistant NHL compared to normal lymphocytes. GST-alpha was not detected in either normal lymphocytes or NHL cells. GST-pi was the predominant isoenzyme, and GST-mu was not detected in chemosensitive NHL. GSH content was significantly lower in chemoresistant NHL compared to other lymphoid tissues tested. The conjugating enzymes UDP-glucuronosyltransferase and sulfatase were similar in either chemoresistant NHL compared to chemosensitive NHL. The activity of the hydrolytic enzyme beta-glucuronidase was lower in chemoresistant compared to chemosensitive NHL, whereas sulfatase was higher in sensitive NHL compared to normal lymphocytes. Epoxide hydrolase was not detected in either normal or NHL cells tested. In conclusion, these studies did not show any cytochrome P-450 in human lymphoid cells tested, but pointed out noteworthy differences for other enzyme systems tested.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Main drug-metabolizing enzyme systems in human non-Hodgkin's lymphomas sensitive or resistant to chemotherapy. 853 97


<< Previous 1 2 3 4 5 Next >>

---