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PubMed1987

Sulphoxidation of albendazole by the FAD-containing and cytochrome P-450 dependent mono-oxygenases from pig liver microsomes.

1. Two distinct microsomal pathways involved in the metabolism of albendazole (ABZ) to albendazole-sulphoxide (SO.ABZ) by pig liver microsomes have been identified and quantified. 2. The binding of ABZ to microsomal cytochrome P-450 (Type I spectrum, Ks = 25.5 microM), the decrease of the rate of sulphoxidation by antibody against NADPH cytochrome c reductase, and the use of purified cytochrome P-450 A demonstrated the contribution of a cytochrome P-450-dependent mono-oxygenase to the metabolism of ABZ. 3. The involvement of FAD-containing mono-oxygenase (FMO) was shown by thermal pretreatment of microsomes, n-octylamine activation of the reaction, and by using purified pig liver FMO. 4. From Km and Vmax values, it would appear that the relative contributions of the two systems depend on the concentration of ABZ.

Albendazole↗
PubMed1991

Quality management: fad or future?

The number-one job of healthcare chief executive officer is to be the standard bearer for quality healthcare delivery, says the top man of the Chicago-based Lutheran General Health Care System, an extensive multicorporate health organization. As long as the CEO remains vigilant and personally responsible for quality at his or her institution, quality management cannot become just a passing fad.

Forecasting↗
PubMed1996

Finding heroes and heroines: fads, fantasies, and foibles of search and screen committees.

Search and screen committees have many agendas other than finding candidates for a job vacancy. They are essentially political processes whereby special interest groups inside and outside the organization can express opinions, monitor diversity, and review and fine-tune the organizational culture with respect to planned change. Search committees reflect the fads of the institutional culture, have fantasies about the kinds of persons they will attract to the position, and commit foibles that may affect the outcome of the search.

Contract Services↗
PubMed1999

Dexamethasone-induced changes in FAD-glycerophosphate dehydrogenase mRNA, content and activity, and insulin release in human pancreatic islets.

Human pancreatic islets were cultured for 63 hr at 2.8 or 16.7 mM D-glucose in the absence or presence of dexamethasone. In the 1.0 to 10 microM range, dexamethasone caused a concentration-related decrease in the FAD (flavin adenine dinucleotide)-linked mitochondrial glycerophosphate dehydrogenase (mGDH) mRNA content of the islets, and decreased both the mGDH content of the islets and the catalytic activity of the enzyme in islet homogenates, these effects being often more marked in islets cultured at 16.7 mM, rather than 2.8 mM, D-glucose. Even after culture in the presence of no more than 10 nM dexamethasone, namely under conditions in which the mGDH mRNA content and activity were both virtually unaffected, the corticosteroid restored the capacity of the beta-cells to display an increase in insulin output in response to a rise in D-glucose concentration in islets first cultured at 2.8 mM D-glucose but suppressed the insulinotropic action of the hexose in islets first cultured at 16.7 mM D-glucose. Whilst revealing an untoward effect of high concentrations of dexamethasone upon mGDH mRNA, content and activity in human islets, these findings also document a dual effect of a low concentration of the corticosteroid (10 nM) upon the secretory responsiveness of human islets to D-glucose, independently of any significant change in mGDH gene expression. It is proposed that such a dual action may account, in part at least, for both the well known increase in insulin output found in hypercorticism and the more recently discovered unfavourable direct effect of corticosteroid hormones on the secretory activity of islet beta-cells.

Adult↗
PubMedDate not supplied

Physician ancillary services: fad or fashion? Part 1.

Ancillary services are quite fashionable in today's medical practice, but perhaps you've wondered if they are only a fad. If you're considering adding services to increase your revenue, you're not too late; this trend seems here to stay. Doing your homework and due diligence is key to the success of your ancillary service. Before introducing a service into your practice or investing in an ancillary venture, make sure that you get off on sound footing. Major investments call for experienced consulting and tapping into financial, operational, and legal specialists to address specific needs. Part 1 of this two-part article defines ancillary services and addresses the following topics: performing the feasibility study; writing the business plan; and addressing the legal and regulatory issues. Part 2 will discuss financing arrangements, opening, operational, and ongoing management elements critical to success.

Decision Making↗
PubMedDate not supplied

Physician ancillary services: fad or fashion? Part 2.

Ancillary services are quite fashionable in today's medical practice, but perhaps you've wondered if they were only a fad. If you're considering adding services to increase your revenue, you're not too late; this trend seems here to stay. Doing your homework and due diligence is key to the success of your ancillary business. Before introducing a service into your practice or investing in an ancillary venture, make sure that you get off on sound footing. Major investments call for experienced consulting and tapping into financial, operational, and legal specialists to address specific needs. Part 1 defined ancillary services and addressed performing the feasibility study and writing the business plan. In this second part, legal and regulatory issues, financing arrangements, opening, and operational and ongoing management elements critical to success are all explored.

Organizational Innovation↗
PubMed1991

Streptozotocin-induced suppression of FAD-linked glycerophosphate dehydrogenase in pancreatic islets of adult rats.

Injection of streptozotocin (30-40 mg/kg body weight) to adult rats caused within 4-6 days a sizeable decrease in the activity of FAD-linked glycerophosphate dehydrogenase in pancreatic islets, with little change in either glutamate dehydrogenase or 2-oxoglutarate dehydrogenase activity. The severity of the enzymatic defect was related to that of the diabetic state, although a decreased enzymic activity was also observed in islets from virtually normoglycemic animals examined 2-3 weeks after streptozotocin injection. The administration of nicotinamide prior to that of streptozotocin prevented the change in enzymic activity. It is proposed that the enzymatic defect, rather than being attributable to a genomic effect of streptozotocin, may reflect the preferential impairment of a subpopulation of pancreatic B-cells.

Animals↗
PubMedDate not supplied

FAD-parametric description of EEG time series.

A new method of the EEG time series parametric description was elaborated. The procedure consists of the following steps: calculation of AR model coefficients, the estimation of the transfer function in the form of parallel filters, finding of the impulse response function parameters. The parameters: frequencies, amplitudes and damaging coefficients (FAD) characterise the basic EEG waves. The average properties of the EEG signals are presented in the form of rhythm diagrams. The method overcomes the difficulties in arbitrary partitioning of the EEG power spectrum into the frequency bands and makes possible the reduction of electroencephalographic data to the few parameters characterising basic rhythms.

Electroencephalography↗
PubMedDate not supplied

Mechanism of azoreduction of dimethylaminoazobenzene by rat liver NADPH-cytochrome P-450 reductase and partially purified cytochrome P-450. Oxygen and carbon monoxide sensitivity and stimulation by FAD and FMN.

We have reported that the hepatocarcinogen dimethylaminoazobenzene (DAB) is reduced by rat liver microsomes in an oxygen- and carbon monoxide-insensitive manner and that activity is induced by clofibrate but no other recognized inducers of cytochrome P-450 activity. In the present study we have shown that the reaction proceeds in a partially purified reconstituted cytochrome P-450 system as well as with purified NADPH-cytochrome P-450 reductase alone. In the latter system, activity is totally inhibited in air whereas the former system is active in air as well as in a carbon monoxide atmosphere. Although clofibrate induces both DAB azoreductase and laurate hydroxylase activities, the suicide substrate 10-undecynoic acid blocks the latter but not the former, implying catalysis by distinct enzymes. FAD and FMN stimulate DAB azoreduction 40-50-fold by both NADPH-cytochrome P-450 reductase alone and by the reconstituted cytochrome P-450 system. However, it was shown that these flavins facilitate electron flow to DAB only from reductase and not from cytochrome P-450. The fact that the reconstituted system, which contains NADPH-cytochrome P-450 reductase, is oxygen insensitive suggests that there is an obligatory electron flow through cytochrome P-450 to DAB, bypassing the oxygen-sensitive step.

Animals↗
PubMed1986

Purification and characterization of FAD synthetase from Brevibacterium ammoniagenes.

The bifunctional enzyme FAD synthetase from Brevibacterium ammoniagenes was purified by a method involving ATP-affinity chromatography. The final preparation was more than 95% pure. The apparent molecular weight of the enzyme was determined as 38,000 and the isoelectric point as 4.6. Although previous attempts to separate the enzymatic activities had failed, ATP:riboflavin 5'-phosphotransferase and ATP:FMN-adenylyltransferase activities in B. ammoniagenes were believed to be located on two separate proteins with similar properties, possibly joined in a complex. The following evidence, however, suggests the presence of both activities on a single polypeptide chain. The two activities copurify in the same ratio through the purification scheme as presented. Only a single band could be detected when aliquots from the final purification step were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis, nondenaturing gel electrophoresis, and isoelectric focusing. Edman degradation of the protein yielded a single N-terminal sequence.

Brevibacterium↗
PubMed1988

Biological properties of ME2303 (FAD-104), a new anthracycline.

ME2303 (FAD-104) is a new anthracycline antibiotic whose structure is characterized by the presence of a 2'-fluoro atom and the lack of a 3'-amino group in the sugar moiety. Its cytocidal activity is superior to or equal to that of adriamycin (ADM). The LD50 value of ME2303 was about 140 mg/kg i.v. in mice and this value was about 7-fold higher than that of ADM. ME2303 was administered intravenously to Golden strain hamsters at doses of 25, 50, 75 and 150 mg/kg and the ECG was examined. From ECG changes, it seems that ME2303 did not show any effect on the heart in acute toxicity. Mutagenicity was recognized as with ADM in the back-mutation test.

Animals↗
PubMed1979

The liver microsomal FAD-containing monooxygenase. Spectral characterization and kinetic studies.

A FAD-containing monooxygenase isolated from pig liver microsomes migrates as a single band upon electrophoresis in polyacrylamide gels in the presence of dodecyl sulfate. The minimum molecular weight based on mass of amino acids per mole of flavin is 64,000. However, the catalytically active enzyme exists as aggregating units of the monomer. Neither oxygen nor organic substrates perturbed the spectrum of the oxidized flavoprotein and their binding to this form of the enzyme could not be detected. Anaerobically NADPH bleaches the flavoprotein, and in the presence of both NADPH and oxygen a remarkably stable intermediate form of the enzyme, with an absorption band at 375 nm, is observed. The spectrum of the intermediate resembles that of a peroxyflavin. The monooxygenase catalyzes NADPH- and oxygen-dependent oxygenations of nucleophilic nitrogen- or sulfur-containing compounds. Kinetic studies carried out with a model organic nitrogen substrate (trimethylamine) and a sulfur substrate (methimazole) gave similar patterns. The kinetic data are consistent with an ordered Ter-Bi mechanism with an irreversible step between the second and third substrate where NADPH is added first, followed by oxygen, and the oxidizable organic substrate is added last. If NADPH is the first substrate added, then NADP+ must be the last product released since NADP+ is competitive with NADPH.

Amino Acids↗
PubMed1983

The large subunit of the fatty acid oxidation complex from Escherichia coli is a multifunctional polypeptide. Evidence for the existence of a fatty acid oxidation operon (fad AB) in Escherichia coli.

The subunit locations of the five enzymes associated with the fatty acid oxidation complex from Escherichia coli were studied by immunotitration and chemical modification. Antibodies raised against the purified complex caused the parallel inhibitions of enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase, while slightly stimulating 3-ketoacyl-CoA thiolase. All five component enzymes of the complex were inactivated by treatment with iodoacetamide. The inactivation of 3-ketoacyl-CoA thiolase was rapid, whereas the four other enzymes were inactivated at much slower, but almost equal rates. All enzymes except for 3-ketoacyl-CoA thiolase were protected against this inactivation by either NADH or crotonyl-CoA. The reaction of iodo[1-14C]acetamide with the complex in the presence and absence of NADH resulted in the differential labeling of the large subunit only. These observations together with published results (Pawar, S., and Schulz, H. (1981) J. Biol. Chem. 256, 3894-3899) lead to the suggestion that enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, cis-delta 3-trans-delta 2-enoyl-CoA isomerase, and 3-hydroxyacyl-CoA epimerase are located on the 78,000-Da subunit, whereas 3-ketoacyl-CoA thiolase is associated with the 42,000-Da subunit. Additionally, this study provides further evidence for the existence of a fatty acid oxidation (fad AB) operon that codes for the multienzyme complex of fatty acid oxidation and that is located at 85 min on the E. coli chromosome.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1981

Separate roles for FMN and FAD in catalysis by liver microsomal NADPH-cytochrome P-450 reductase.

Rat liver microsomal NADPH-cytochrome P-450 reductase was prepared free of detectable amounts of FMN by a new procedure based on the exchange of this flavin into apoflavodoxin. The resulting FMN-free reductase binds NADP in the oxidized state with the same affinity (Kd = 5 microM) and stoichiometry (1:1 molar ratio) as does the native enzyme. Both the native and FMN-free reductase catalyze rapid reduction of ferricyanide, but the ability to reduce th 5,6-benzoflavone-inducible form of the liver microsomal cytochrome P-450 (P-450LM4) is lost upon removal of FMN. The FMN-free enzyme was reconstituted with artificial flavins which, in the free state, have oxidation-reduction potentials ranging from -152 to -290 mV, including 5-carba-5-deaza-FMN and several FMN analogs with a halogen or sulfur substituent on the dimethylbenzene portion of the ring system. Enzyme reconstituted with 5-carba-5-deaza-FMN has catalytic properties which are not significantly different from those of the FMN-free reductase, and is unable to reduce P-450LM4. On the other hand, the ability to reduce P-450LM4 and the other FMN-dependent activities of the native reductase are restored by substitution of several other analogs for FMN, but the kinetics of P-450LM4 reduction, studied under anaerobic conditions by stopped flow spectrophotometry, are significantly altered. The oxidation-reduction behavior of enzyme reconstituted with 7-nor-7-Br-FMN is substantially different from that of the native enzyme, and less thermodynamic stabilization of the semiquinone is observed with this flavin analog. In contrast, the oxidation-reduction properties of enzyme containing 8-nor-8-mercapto-FMN are similar to those of the native enzyme, but the spectral properties are significantly different. As shown in a stopped flow experiment, reduction of this FMN analog precedes reduction of P-450LM4 when a complex of the flavoprotein and P-450LM4 is allowed to react with NADPH. Our experiments support a sequence of electron transfer in this enzyme system as follows: NADPH leads to FAD leads to FMN leads to P-450. We propose that the enzyme cycles between a le- and a 3e-reduced state during turnover and that electrons are donated to acceptors via the reaction, FMNH2 leads to FMNH ..

Animals↗
PubMed1982

Studies on FAD- and FMN-binding domains in NADPH-cytochrome P-450 reductase from rabbit liver microsomes.

Six sulfhydryl group were determined after complete denaturation of NADPH-cytochrome P-450 reductase; of these, about 5.2 in both the native holoenzyme and FMN-depleted enzyme are accessible to p-hydroxychloromercuribenzoate (pCMB), which may be differentiated as follows: four --SH groups are modified by low concentration of the reagent but are not essentially involved in the catalytic function; additional block of one --SH group at high concentrations of pCMB completely inhibited the reductase activity. The fluorescence quenching of the FAD in the FMN-depleted enzyme was removed after the fifth --SH group was reacted slowly with pCMB. Kinetic and fluorometric analysis indicated that this finally modified --SH group was assumed to be essential for the activity and significantly protected by either 1 mM NADP+ or 2'-AMP against attack by mercurial compounds. A strong negative ellipticity at around 450 nm is clearly decreased upon binding of pCMB to an essential --SH group, while the CD spectra in the near and far UV region show only minor differences during the modification of --SH groups. Removal of the FMN prosthetic group from the native holoprotein results in 1.25-fold greater tryptophan fluorescence with a slight red shift of the emission maximum from 332 to 336 nm, and FMN reconstitution reduces the protein fluorescence quantum yield to approximately that of the holoprotein. Oxidation of tryptophan indol rings of the FMN-depleted enzyme is associated with a loss of FMN binding ability to the protein which causes the inactivation of cytochrome c reductase activity, but ferricyanide reductase activity is not strongly affected by tryptophan modification.

Animals↗
PubMed1981

The oxidative half-reaction of liver microsomal FAD-containing monooxygenase.

The reactions of reduced forms of liver microsomal FAD-containing monooxygenase both with oxygen and with several oxygenatable substrates have been investigated using rapid reaction techniques. It was first shown that the pH optimum was at about 8.8 and that at pH values below 8 the stoichiometry was very nearly 1:1:1 for NADPH/(cysteamine or methimazole)/oxygen consumption, with only traces of H2O2 forming. Low temperatures (approximately 4 degrees C) were employed to better resolve kinetic intermediates occurring in the reaction. It was shown that in the absence of NADP+, substrate has no effect on the rate of reoxidation of reduced enzyme by O2. However, in the presence of NADP+ and the absence of substrate, the reduced enzyme reacts with O2 to form a remarkably stable C(4a)-hydroperoxyflavin species. This occurs in a reaction that saturates with respect to O2, implying the formation of a reversible complex with oxygen prior to the formation of the hydroperoxyflavin. This has been predicted by the steady state kinetics (Poulsen, L. L., and Ziegler, D. M. (1979) J. Biol. Chem. 254, 6449-6455). In the presence of NADP+, substrate increases the rate of reoxidation (by destabilizing the hydroperoxyflavin), but the rate is much slower than the reaction of reduced enzyme with O2 in the absence of NADP+. The stability of the hydroperoxyflavin permitted its preparation on the stopped flow apparatus for subsequent reaction with various substrates. This reaction involved the rapid formation of a species with a new spectrum which was indicative of a C(4a)-substituted flavin. Since this new species converts to oxidized flavin at about 2 min-1, which is equivalent to Vmax, it must be the rate-limiting step in the catalytic reaction. This new spectrum is likely due either to a substrate-hydroperoxyflavin species or to a product-hydroxyflavin species.

Aniline Compounds↗
PubMed1980

Characterization of the purified NADH-cytochrome b5 reductase of human erythrocytes as a FAD-containing enzyme.

NADH-cytochrome b5 reductase of normal human erythrocytes was purified by procedures including affinity chromatography on Blue-Sepharose to an electrophoretically homogeneous protein. The purified enzyme was judged to be a typical flavoprotein based on its absorption spectrum (absorption maxima, 272, 390, and 462 nm; shoulders, 373 and 488 nm) and flavin content (1 mol of FAD/mol of enzyme). The minimum molecular weight calculated from the flavin content was 32,300. The purified enzyme showed a distinct negative circular dichroic spectrum at 280 nm and also at 460 to 480 nm. With the best preparations, the molar ellipticities at 280 and 460 nm were well correlated with the enzyme activity and flavin content in the enzyme. A partial loss of flavin from the enzyme led to a concomitant loss of enzyme activity and decrease in the molar ellipticities at 460 and 280 nm. Flavin analogues such as acrinol and proflavine (0.1 mM) strongly inhibited the enzyme activity, and atebrin (0.1 mM) also showed partial inhibition. Complete inhibition was observed with 1 mM of any these reagents. These results apparently indicate that FAD in the enzyme functions as a prosthetic group, and that circular dichroic spectroscopy is a good measure of the bound form of flavin in the enzyme.

Animals↗