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The Journal of Biological Chemistry Feb 1987ermC encodes a methylase that modifies 23 S rRNA, conferring resistance to macrolide-lincosamide-streptogramin B antibiotics. The expression of this gene is induced by...
ermC encodes a methylase that modifies 23 S rRNA, conferring resistance to macrolide-lincosamide-streptogramin B antibiotics. The expression of this gene is induced by erythromycin using a translational mechanism. We have employed the inherent RNase activity of a Bacillus subtilis S-30 extract as a probe for studying the interaction of ribosomes with ermC mRNA in the presence of antibiotics. 5' end-labeled ermC runoff transcript is a substrate for this RNase activity, while the ribosome-bound region of the RNA appears to be protected. Erythromycin- and oleandomycin-dependent protection of fragments of length 79-81 was observed during the translation of end-labeled ermC transcript. This occurs only using unmethylated (erythromycin sensitive) ribosomes. Various other antibiotics including clindomycin, tylosin, and lincomycin do not show this specific protection. These effects parallel the in vivo specificity of ermC induction. The effect of erythromycin can be abolished by using oligonucleotides complementary to regions of the ermC transcript upstream from nucleotide 71 and not by using an oligonucleotide complementary to a region of ermC downstream from that position. These results are interpretable in terms of the translational attenuation model and demonstrate that erythromycin-bound ribosomes initiate translation of the leader peptide, stall upstream from nucleotide 80 on the ermC mRNA, and thus make the ribosome-binding site for methylase message available for ribosome interaction.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Erythromycin; Nucleic Acid Conformation; Protein Biosynthesis; Protein Sorting Signals; RNA, Messenger; Ribosomes; Transcription, Genetic
PubMed: 3027099
DOI: No ID Found -
British Medical Journal Jul 1968
Topics: Drug Resistance, Microbial; Erythromycin; Humans; Leucomycins; Lincomycin; Oleandomycin; Osteomyelitis; Staphylococcus
PubMed: 5662980
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Aug 1989Macrolide 2'-phosphotransferase [MPH(2')] was purified 90-fold from an erythromycin-resistant strain of Escherichia coli, and its enzymatic properties were investigated....
Macrolide 2'-phosphotransferase [MPH(2')] was purified 90-fold from an erythromycin-resistant strain of Escherichia coli, and its enzymatic properties were investigated. MPH(2') is an inducible intracellular enzyme which showed high levels of activity with 14-member-ring macrolides and extremely low levels with 16-member-ring macrolides. The optimum pH for inactivation of oleandomycin was 8.2, and the optimum temperature of the reaction was 40 degrees C. Enzyme activity was lost by heat treatment at 50 degrees C for 1 min. The isoelectric point and molecular weight of the enzyme were 5.3 and 34,000, respectively. Purine nucleotides, such as GTP, ITP, and ATP, were effective as cofactors in the inactivation of macrolides. Iodine, EDTA, or divalent cations inhibited MPH(2') activity.
Topics: Anti-Bacterial Agents; Culture Media; Drug Resistance, Microbial; Electrophoresis, Polyacrylamide Gel; Enzyme Induction; Erythromycin; Escherichia coli; Indicators and Reagents; Isoelectric Focusing; Microbial Sensitivity Tests; Phosphotransferases; Phosphotransferases (Alcohol Group Acceptor); Staining and Labeling
PubMed: 2478074
DOI: 10.1128/AAC.33.8.1354 -
British Journal of Pharmacology Oct 2006The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore,... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats.
EXPERIMENTAL APPROACH
Metformin at a dose of 100 mg kg(-1) was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3-methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF-525 (a non-specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time-averaged non-renal clearance (CLNR) of metformin was compared with that of controls.
KEY RESULTS
In rats pretreated with dexamethasone, the CLNR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CLNR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNR values did not significantly different in the rats pretreated with 3-methylencholanthrene, orphenadrine, and isoniazid compared with the controls.
CONCLUSIONS AND IMPLICATIONS
Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.
Topics: Alcohol Oxidoreductases; Animals; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P450 Family 2; Dexamethasone; Enzyme Induction; Enzyme Inhibitors; Hypoglycemic Agents; Liver; Male; Membrane Proteins; Metformin; Protein Binding; Quinine; Rats; Rats, Sprague-Dawley; Steroid 16-alpha-Hydroxylase; Sulfaphenazole; Troleandomycin
PubMed: 16940989
DOI: 10.1038/sj.bjp.0706875 -
Journal of Bacteriology Apr 1965Mitsuhashi, Susumu (Gunma University, Maebashi, Japan), Hajime Hashimoto, Megumi Kono, and Masato Morimura. Drug resistance of staphylococci. II. Joint elimination and...
Mitsuhashi, Susumu (Gunma University, Maebashi, Japan), Hajime Hashimoto, Megumi Kono, and Masato Morimura. Drug resistance of staphylococci. II. Joint elimination and joint transduction of the determinants of penicillinase production and resistance to macrolide antibiotics. J. Bacteriol. 89:988-992. 1965.-Strains of Staphylococcus aureus, which show high resistance to macrolide antibiotics (erythromycin, oleandomycin, leucomycin, and spiramycin) and the capacity to produce penicillinase, have been isolated from clinical sources. The determinants of penicillinase production (PCase(+)) and resistance to macrolide antibiotics (MAC(r)) of these strains were irreversibly eliminated by treatment with acridine or with ultraviolet light. Among the 18 strains tested, PCase(+) and MAC(r) were eliminated from all strains except one, which lost only PCase(+) but not MAC(r). The characters PCase(+) and MAC(r) were jointly transduced with the aid of phage lysates, obtained from the resistant donors by ultraviolet irradiation, into staphylococcal strains sensitive to PC and MAC. Segregation of PCase(+) and MAC(r) was rarely observed after transduction. From these results, it is suggested that the determinants of both PCase(+) and MAC(r) of staphylococci are located close together on a single genetic element, i.e., a plasmid (or episome), which exists extrachromosomally.
Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Erythromycin; Humans; Japan; Macrolides; Oleandomycin; Penicillinase; Radiation Effects; Research; Spiramycin; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Ultraviolet Rays
PubMed: 14276126
DOI: 10.1128/jb.89.4.988-992.1965 -
Drug Metabolism and Pharmacokinetics 2013Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory...
Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory effects of GTE on CYP3A activity were investigated in rat hepatic microsomes (RHM) using midazolam (MDZ) 1'-hydroxylation as a probe reaction. SD female rats received a single oral dose of GTE (400 mg/kg) or troleandomycin (TAO, a CYP3A selective inhibitor, 500 mg/kg), followed 30 min later by SIM (20 mg/kg). Plasma concentrations of SIM and its active metabolite, simvastatin acid, were determined up to 6 h after the SIM administration using LC/MS/MS. In RHM, GTE inhibited MDZ 1'-hydroxylation with IC₅₀ and K(i)(app) values of 12.5 and 18.8 µg/mL, respectively, in a noncompetitive manner. Area under plasma concentration-time curves for SIM in the GTE and TAO groups were increased by 3.4- and 10.2-fold, respectively, compared with the control. The maximum concentrations of SIM were higher in the GTE (3.3-fold) and TAO (9.5-fold) groups. GTE alters the pharmacokinetics of SIM, probably by inhibiting intestinal CYP3A.
Topics: Animals; Camellia sinensis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Female; Microsomes, Liver; Midazolam; Plant Extracts; Rats; Simvastatin; Troleandomycin
PubMed: 23698259
DOI: 10.2133/dmpk.dmpk-13-nt-006 -
The Journal of Antibiotics Apr 1975Growing cultures, as well as broken and lyophilized cells of pseudomonas 56 were found to degrade erythromycin A, and lyophilized cells inactivated erythromycins A and...
Growing cultures, as well as broken and lyophilized cells of pseudomonas 56 were found to degrade erythromycin A, and lyophilized cells inactivated erythromycins A and B. The enzyme system involved in this degradation was constitutive and the enzyme level in the cells could be increased about 8-fold when oleandomycin or erythromycin B was added to the growth medium. The ability of whole or broken cells to inactivate erythromycin A was completely lost when these preparations were boiled, and the erythromycin A-inactivating activity was localized in the cell membrane fraction. The lyophilized cells did not degrade oleandomycin, methymycin, tylosin, a mixture of leucomycins, josamycin, or maridomycin III.
Topics: Anti-Bacterial Agents; Biodegradation, Environmental; Biological Assay; Chromatography, Thin Layer; Erythromycin; Freeze Drying; Pseudomonas; Sarcina; Staphylococcus
PubMed: 1150530
DOI: 10.7164/antibiotics.28.307 -
Xenobiotica; the Fate of Foreign... Nov 2020Time-dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis...
Time-dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis of microsomal assays. Additionally, a distinct terminal inactivation step was identified for certain mechanism based inhibitors (MBI) following reversible metabolite intermediate complex (MIC) formation. Longer hepatocyte incubations potentially allow analysis of slow TDI and terminal inactivation. In the experiments presented here, we compared the quality of TDI parameterization by numerical analysis between hepatocyte and microsomal data. Rat liver microsomes (RLM), suspended rat hepatocytes (SRH) and sandwich-cultured rat hepatocytes (SCRH) were incubated with the prototypical CYP3A MBI troleandomycin and the substrate midazolam. Data from RLM provided a better model fit as compared to SRH. Increased CYP3A expression after dexamethasone (DEX) induction improved the fit for RLM and SRH. A novel sequential kinetic scheme, defining inhibitor metabolite production prior to MIC formation, improved the fit compared to direct MIC formation. Furthermore, terminal inactivation rate constants were parameterized for RLM and SRH samples with DEX-induced CYP3A. The low expression of CYP3A and experimental error in SCRH resulted in poor data for model fitting. Overall, RLM generated data better suited for elucidation of TDI mechanisms by numerical analysis.
Topics: Animals; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Hepatocytes; Kinetics; Microsomes, Liver; Models, Biological; Rats; Troleandomycin
PubMed: 28644704
DOI: 10.1080/00498254.2017.1345020 -
Journal of Clinical Microbiology Jun 1987A selective agar medium for isolation of virulent Yersinia enterocolitica (VYE agar) was developed for the rapid and accurate isolation of virulent Y. enterocolitica... (Comparative Study)
Comparative Study
A selective agar medium for isolation of virulent Yersinia enterocolitica (VYE agar) was developed for the rapid and accurate isolation of virulent Y. enterocolitica from environmental samples highly contaminated with environmental Yersinia organisms, as well as for isolation from clinical specimens. VYE agar provided a quantitative recovery of 51 different strains of virulent Y. enterocolitica at 32 degrees C after incubation for 24 h. The cefsulodin, irgasan, josamycin, and oleandomycin content of the medium resulted in a high selectivity, and the mannitol and esculin content provided some differentiation. The greatest advantage of VYE agar is that virulent Y. enterocolitica, which forms red colonies, is easily differentiated from most environmental Yersinia organisms and other gram-negative bacteria, which form dark colonies with a dark peripheral zone as a result of esculin hydrolysis. Use of VYE agar led to a high recovery of Y. enterocolitica biotype 3B serotype O:3 strains from experimentally inoculated meat samples, compared with use of CIN agar. Biotype 2 serotypes O:5,27 and O:9 and biotype 1 esculin-negative serotypes O:4,32, O:8, O:13a,13b, O:18, O:20, and O:21 (American types) were readily differentiated from other environmental organisms able to grow on VYE agar. Epidemiological studies on Y. enterocolitica should be greatly facilitated by the use of this selective agar medium.
Topics: Animals; Culture Media; Feces; Humans; Meat; Swine; Virulence; Yersinia enterocolitica
PubMed: 3597750
DOI: 10.1128/jcm.25.6.1068-1073.1987 -
Journal of Clinical Pathology Aug 1972Strains of Staphylococcus aureus isolated from the lesions of hospital patients were surveyed for resistance to sulphamethoxazole and to trimethoprim. Of 675 strains...
Strains of Staphylococcus aureus isolated from the lesions of hospital patients were surveyed for resistance to sulphamethoxazole and to trimethoprim. Of 675 strains tested, 18.5% were resistant to sulphamethoxazole and 1.6% to trimethoprim. All the trimethoprim-resistant strains were resistant to sulphamethoxazole and to a 1:20 mixture of the two drugs. Trimethoprim-resistant strains were on average more resistant to sulphamethoxazole than were trimethoprim-sensitive strains. They were all resistant to several other antimicrobial agents. Most of them had the phage-typing pattern 84/85, 84, or 85.
Topics: Anti-Bacterial Agents; Bacitracin; Bacteriophage Typing; Drug Resistance, Microbial; Folic Acid Antagonists; Fusidic Acid; Humans; Lincomycin; Microbial Sensitivity Tests; Neomycin; Oleandomycin; Penicillin Resistance; Pyrimidines; Staphylococcus; Streptomycin; Sulfamethoxazole; Sulfonamides; Tetracycline; Trimethoprim
PubMed: 5076806
DOI: 10.1136/jcp.25.8.708