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PubMed1984

The thermodynamics of flavin binding to the apoflavodoxin from Azotobacter vinelandii.

A thermodynamic study of the binding of flavins (FMN, FAD, 8-carboxylic acid-riboflavin) to the purified apoflavodoxin from Azotobacter vinelandii has been conducted. The binding of FMN was studied at a number of temperatures (10, 15, 20, 25, and 30 degrees C), pH's (6.0, 7.4, and 9.0), and buffer conditions. The binding of FAD was studied at pH 7.4 and 25 degrees C under a number of buffer conditions. The binding of 8-carboxylic acid-riboflavin to the apoflavodoxin and the binding of FMN to the dimeric form of the apoflavodoxin were investigated at pH 7.4 and 25 degrees C. Enthalpies of binding for FMN, FAD, and 8-carboxylic- acid-riboflavin were -28.3, -16.6, and -14.0 kcal mol-1, respectively. The enthalpy of binding of FMN to the dimeric form of the apoflavodoxin was -22.2 kcal mol of binding sites-1. Binding constants of about 10(8), 10(6), and 10(6) were obtained for the binding of FMN, FAD, and 8-carboxylic acid-riboflavin, respectively. Using established thermodynamic relationships free energy and entropy changes were calculated. The entropy data indicate that a large degree of ordering of the system occurs upon flavin binding. The pH data suggest that FMN may bind in both the mono- and dianion forms, and that binding doesn't change the pKa of any functional group in the system. It appears that the phosphate group is probably responsible for approximately half the binding enthalpy observed for the binding of FMN. The temperature-dependence data over the temperature range studied is biphasic, centered at 20 degrees C, indicating that flavin binding occurs to the protein in two thermodynamic states corresponding to the two heat capacities observed. These findings are used to discuss a model for flavin binding.

Apoproteins↗
PubMed1985

Flavocytochromes c: transient kinetics of photoreduction by flavin analogues.

Kinetics of reduction of phototrophic bacterial flavocytochromes c by exogenous flavin semiquinones and fully reduced flavins generated by laser flash photolysis have been studied. The mechanisms of reduction of Chromatium and Chlorobium flavocytochromes c are more similar to one another than previously thought. Neither protein is very reactive with neutral flavin semiquinones (k less than 10(7) M-1 s-1), and the reactions with fully reduced flavins are slower than expected on the basis of comparison with other electron-transfer proteins of similar redox potentials. Deazaflavin radical is reactive with the flavocytochromes c by virtue of its low redox potential, but this reaction is also slower than expected on the basis of comparison with other electron-transfer proteins. These experiments indicate that the active site for reduction of flavocytochrome c is relatively buried and probably inaccessible to solvent. Fully reduced FMN does not show an ionic strength effect in its reaction with flavocytochrome c, which demonstrates that the active site is uncharged. Sulfite, which forms an adduct with protein-bound FAD, partially blocks heme reduction. This shows that heme is reduced via the FAD. The rate constant for intramolecular electron transfer between FAD and heme must be on the order of 10(4) s-1 or larger.

Bacteria↗
PubMed1981

Photoreception in Neurospora crassa: correlation of reduced light sensitivity with flavin deficiency.

The effect of flavin deficiency on blue light responses in Neurospora crassa was studied through the use of two riboflavin mutants (rib-1 and rib-2). The photoresponses assayed were the suppression of circadian conidiation, the phase shifting of the circadian conidiation rhythm, and the induction of carotenoid synthesis. Flavin deficiency was induced in the rib-1 mutant by restrictive growth temperatures and in the rib-2 mutant by low levels of supplemental riboflavin. At 26 degrees C, a semirestrictive growth temperature, the rib-1 mutant is about 1/80th as sensitive to light for the photosuppression of circadian conidiation. Flavin deficiency in the rib-1 and rib-2 strains was effective in reducing the photosensitivity for phase shifting and carotenogenesis to about 1/16th and 1/4th of normal, respectively. Experiments with permissive temperatures, riboflavin supplementation, and revertants at the rib locus all indicated that the effects on light sensitivity were due solely to the presence of the rib mutations. These results provide evidence that one or more flavin photoreceptors are involved in the blue light responses of Neurospora.

Carotenoids↗
PubMed2001

Modulating the redox property of a flavin analog through adjustment of its microenvironment in a self-assembled monolayer.

Self-assembled monolayers (SAMs) have been used to examine the effects of electrostatic interactions and changing microenvironment on the pH-dependent redox properties of a flavin analog. The pKa value of the N1 proton for the reduced flavin analog was determined to be approximately 9.7 in the SAM of disulfide 5, 8.5 in the SAM of disulfide 7, and 6.7 when free in solution. The pyridinium ion of 7 stabilizes the anionic form of reduced flavin analog and provides a dielectric medium more closely resemblingthat experienced by the flavin analog free in solution.

Disulfides↗
PubMed2004

Catalytic photooxidation of 4-methoxybenzyl alcohol with a flavin-zinc(II)-cyclen complex.

Flavin-zinc(II)-cyclen 10 contains a covalently linked substrate binding site (zinc(II)-cyclen) and a chromophore unit (flavin). Upon irradiation, compound 10 effectively oxidizes 4-methoxybenzyl alcohol (11-OCH3) to the corresponding benzaldehyde both in water and in acetonitrile. In the presence of air, the reduced flavin 10-H2 is reoxidized, and so catalytic amounts of 10 are sufficient for alcohol conversion. The mechanism of oxidation is based on photoinduced electron transfer from the coordinated benzyl alcohol to the flavin chromophore. This intramolecular process provides a much higher photooxidation efficiency, with quantum yields 30 times those of the comparable intermolecular process with a flavin chromophore without a binding site. For the reaction in buffered aqueous solution a quantum yield of Phi = 0.4 is observed. The turnover number in acetonitrile is increased (up to 20) by high benzyl alcohol concentrations. The results show that the covalent combination of a chromophore and a suitable binding site may lead to photomediators more efficient than classical sensitizer molecules.

Journal Article↗
PubMed1985

Catalytic activity and substrate specificity of the flavin-containing monooxygenase in microsomal systems: characterization of the hepatic, pulmonary and renal enzymes of the mouse, rabbit, and rat.

Inhibitory antibodies against NADPH-cytochrome P-450 reductase, detergent solubilization to dissociate functional interaction between the reductase and cytochrome P-450, and selective trypsin degradation have been used to characterize flavin-containing monooxygenase activity in microsomes from different tissues and species. A comparison of assay methods is reported. The native microsome-bound flavin-containing monooxygenase of mouse, rabbit, and rat liver, lung, and kidney can metabolize compounds containing thiol, sulfide, thioamide, secondary and tertiary amine, hydrazine, and phosphine substituents. Therefore, this enzyme from these common experimental animals has catalytic capabilities similar to those of the well-characterized porcine liver enzyme. True allosteric activation by n-octylamine does not appear to be a property of either the mouse, rabbit, or rat liver enzymes, but is a property of the pig liver and mouse lung enzymes. The microsomal pulmonary flavin-containing monooxygenase of the rabbit has some unique substrate preferences which differ from the mouse lung enzyme. Both the rabbit and mouse pulmonary enzymes have recently been shown to be distinct enzyme forms. However, the rat pulmonary flavin-containing monooxygenase appears to be catalytically identical to the rat liver enzyme, and does not have any of the unusual catalytic properties of either the rabbit or mouse lung enzymes. Enzyme activity of mouse, rabbit, and rat kidney microsomes is qualitatively similar to the hepatic activities. Substrates which saturate the microsome-bound flavin-containing monooxygenase at 1.0 mM, including thiourea, thioacetamide, methimazole, cysteamine, and thiobenzamide, are metabolized at common maximal velocities. This suggests that the kinetic mechanism of the native enzyme is similar to that established for the isolated porcine liver enzyme in that the rate-limiting step of catalysis occurs after substrate binding, and that all substrates capable of saturating the microsomal enzyme should be metabolized at a common maximal velocity.

Animals↗
PubMed1993

Catalytic activity and immunohistochemical localization of flavin-containing monooxygenase in rat kidney.

The presence of flavin-containing monooxygenase activity was examined in rat kidney microsomes using N,N-dimethylaniline and methimazole as substrates. Western immunoblot analysis using antisera to porcine liver and rabbit lung flavin-containing monooxygenase indicated immunological cross-reactivity between rat kidney, porcine liver and rabbit lung flavin-containing monooxygenase. Immunohistochemical studies using antisera to rabbit lung flavin-containing monooxygenase demonstrated localization of this enzyme in the proximal and distal convoluted tubules of the renal cortex, the collecting ducts in the renal medulla, but not the glomeruli. This observation indicates the colocalization of flavin-containing monooxygenase and cytochrome P-450 in the metabolically active and absorptive compartment of the renal parenchyma.

Aniline Compounds↗
PubMed1980

Purification and properties of NADPH:flavin oxidoreductase from Entamoeba histolytica.

Amebal NADPH:flavin oxidoreductase was purified to apparent homogeneity. Molecular weights of 40 000 and 38 000 were estimated by gel filtration and by sodium dodecyl sulfate polyacrylamide gel electrophoresis, respectively, indicating that the enzyme is composed of a single polypeptide chain. The enzyme does not contain firmly bound flavin. It exhibited 20-fold selectivity for NADPH over NADH. With the former donor it reduced riboflavin, galactoflavin, FMN, or FAD. Aerobically the reducing equivalents were passed from reduced flavin to oxygen to form hydrogen peroxide. Intact amebae do not produce peroxide when they respire. If the title enzyme functions to reduce flavin in the intact cells some electron carrier must intervene between reduced flavin and oxygen so that the final step produces water instead of peroxide.

Amino Acids↗
PubMed1976

Structural elucidation and properties of 8alpha-(N1-histidyl)riboflavin: the flavin component of thiamine dehydrogenase and beta-cyclopiazonate oxidocyclase.

In addition to 8alpha-(N3-histidyl)riboflavin, 8alpha-(N1-histidyl)riboflavin is also formed during the reaction of Nalpha-blocked histidine with 8alpha-bromotetraacetylriboflavin in a yield of 20-25% of the total histidylflavin fraction. The properties of 8alpha-(N1-histidyl)riboflavin are inditical with those of the histidylflavin isolated from thiamine dehydrogenase and beta-cyclopiazonate oxidocyclase but differ from those of 8alpha-(N3-histidyl)riboflavin. These properties include pKa of fluorescence quenching, electrophoretic mobility at pH 5.0, stability to storage, and reduction by NaBH4. Proof for 8alpha substitution is shown by the electron paramagnetic resonance and electron-nuclear double resonance spectra of the cationic semiquinone form, as well as by the proton magnetic resonance spectrum of the oxidized form. The site of histidine substitution by the 8alpha-methylene of the flavin moiety was shown by methylation of the imidazole ring with methyl iodide, cleavage of the methylhistidine-flavin bond by acid hydrolysis at 150 degrees C, and identification of the methylhistidine isomer by electrophoresis. 3-Methylhistidine is the product from the N1-histidylflavin isomer, while 1-methylhistidine is produced from the N3 isomer. The flavin product from reductive Zn cleavage of either isomer has been identified as riboflavin. The compound obtained on acid treatment of 8alpha-(N3-histidyl)riboflavin (previously thought to be the N1 isomer) differs from the parent compound only in the ribityl side chain, since chemical degradation studies show 1-methylhistidine as a product and a flavin product which differs from riboflavin only in mobility in thin-layer chromatography, but not in absorption, fluorescence, and electron paramagnetic resonance spectral properties. Proof that acid modification involves only the ribityl chain has come from the observations that alkaline irradiation of this flavin yields lumiflavin, that the proton magnetic resonance spectrum of the compound differs from that of riboflavin in the region of the ribityl proton resonance, and that its periodate titer is lower than that of authentic riboflavin. The identity of 8alpha-(N1-histidyl)riboflavin with the histidylflavin from thiamine dehydrogenase and beta-cyclopiazonate oxidocyclase shows that both isomeric forms of 8alpha-histidylflavin occur in nature.

Alcohol Oxidoreductases↗
PubMed1982

Evidence from studies with acifluorfen for participation of a flavin-cytochrome complex in blue light photoreception for phototropism of oat coleoptiles.

The diphenyl ether acifluorfen enhances the blue light-induced absorbance change in Triton X100-solubilized crude membrane preparations from etiolated oat (Avena sativa L. cv. Lodi) coleoptiles. Enhancement of the spectral change is correlated with a change in rate of dark reoxidation of a b-type cytochrome. Similar, although smaller, enhancement was obtained with oxyfluorfen, nitrofen, and bifenox. Light-minus-dark difference spectra in the presence and absence of acifluorfen, and the dithionite-reduced-minus oxidized difference spectrum indicate that acifluorfen is acting specifically at a blue light-sensitive cytochrome-flavin complex. Sodium azide, a flavin inhibitor, decreases the light-induced absorbance change significantly, but does not affect the dark reoxidation of the cytochrome. Hence, it is acting on the light reaction, suggesting that the photoreceptor itself is a flavin. Acifluorfen sensitizes phototropism in dark-grown oat seedlings such that the first positive response occurs with blue light fluences as little as one-third of those required to elicit the same response in seedlings grown in the absence of the herbicide. Both this increase in sensitivity to light and the enhancement of the light-induced cytochrome reduction vary with the applied acifluorfen concentration in a similar manner. The herbicide is without effect either on elongation or on the geotropic response of dark-grown oat seedlings, indicating that acifluorfen is acting specifically close to, or at the photoreceptor end of, the stimulus-response chain. It seems likely that the flavin-cytochrome complex serves to transduce the light signal into curvature in phototropism in oats, with the flavin moiety itself serving as the photoreceptor.

Journal Article↗
PubMed1996

Cys5 and Cys214 of NAD(P)H:flavin oxidoreductase from Escherichia coli are located in the active site.

The NAD(P)H:flavin oxidoreductase (NADPH:riboflavin oxidoreductase) from Escherichia coli, Fre, is a monomer of 26.1 kDa, which catalyzes the reduction of free flavins by NADPH or NADH. A sequential ordered mechanism, with NADPH binding first, operates. Fre is the prototype of a class of flavin reductases able to transfer electrons with no prosthetic group. It has been previously reported that several members of this family, including Fre, were inactivated by thiol reagents such as N-ethylmaleimide (MalNEt). Amino acid sequence similarities among these enzymes reveal that one of the three cysteines residues of Fre is highly conserved. Altogether this suggested a crucial role of cysteine residues for catalysis. The three cysteine residues were mutated to serine residues. Single-mutant and double-mutant enzymes were as active as the wild-type and Km values for both substrates remained the same. Cysteine residues are thus not important for activity. Nevertheless, we showed that cysteines 5 and 214, but not cysteine 149, were responsible for MalNEt inactivation. In addition, it has been found that riboflavin, but not NADPH, can protect Fre from MalNEt inactivation. This strongly suggested that Cys5 and Cys214 are located at the flavin-binding site of Fre and that flavin can bind to the enzyme in the absence of NADPH.

Amino Acid Sequence↗
PubMed1993

Detection of radical ion intermediates in flavin-photosensitized pyrimidine dimer splitting.

Photosensitized splitting of cis-syn- and trans-syn-1,3-dimethyluracil dimers by 2',3',4',5'-tetraacetylriboflavin in acetonitrile containing a trace of perchloric acid was studied by laser flash photolysis. Protonation of the flavin prior to excitation resulted in excited singlet and triplet states that abstracted an electron from the dimers and yielded the protonated flavin radical (FlH2.+), which was detected by absorption spectroscopy. Electron abstraction by the excited singlet state predominated over abstraction by the triplet state. Approximately one-third to one-half of the excited states quenched by the trans-syn dimer yielded FlH2.+, the balance presumably undergoing back electron transfer within the geminate radical ion pair generated by the initial electron transfer. A covalently linked dimer-flavin exhibited very inefficient flavin radical ion formation, consistent with the known low efficiency of dimer splitting in this system. These results constitute the first identification of a flavin radical ion intermediate in photosensitized pyrimidine dimer splitting.

Free Radicals↗
PubMed2000

The function of cytoplasmic flavin reductases in the reduction of azo dyes by bacteria.

A flavin reductase, which is naturally part of the ribonucleotide reductase complex of Escherichia coli, acted in cell extracts of recombinant E. coli strains under aerobic and anaerobic conditions as an "azo reductase." The transfer of the recombinant plasmid, which resulted in the constitutive expression of high levels of activity of the flavin reductase, increased the reduction rate for different industrially relevant sulfonated azo dyes in vitro almost 100-fold. The flavin reductase gene (fre) was transferred to Sphingomonas sp. strain BN6, a bacterial strain able to degrade naphthalenesulfonates under aerobic conditions. The flavin reductase was also synthesized in significant amounts in the Sphingomonas strain. The reduction rates for the sulfonated azo compound amaranth were compared for whole cells and cell extracts from both recombinant strains, E. coli, and wild-type Sphingomonas sp. strain BN6. The whole cells showed less than 2% of the specific activities found with cell extracts. These results suggested that the cytoplasmic anaerobic "azo reductases," which have been described repeatedly in in vitro systems, are presumably flavin reductases and that in vivo they have insignificant importance in the reduction of sulfonated azo compounds.

Aerobiosis↗
PubMed1993

Characterization of the baiH gene encoding a bile acid-inducible NADH:flavin oxidoreductase from Eubacterium sp. strain VPI 12708.

A cholate-inducible, NADH-dependent flavin oxidoreductase from the intestinal bacterium Eubacterium sp. strain VPI 12708 was purified 372-fold to apparent electrophoretic homogeneity. The subunit and native molecular weights were estimated to be 72,000 and 210,000, respectively, suggesting a homotrimeric organization. Three peaks of NADH:flavin oxidoreductase activity (forms I, II, and III) eluted from a DEAE-high-performance liquid chromatography column. Absorption spectra revealed that purified form III, but not form I, contained bound flavin, which dissociated during purification to generate form I. Enzyme activity was inhibited by sulfhydryl-reactive compounds, acriflavine, o-phenanthroline, and EDTA. Activity assays and Western blot (immunoblot) analysis confirmed that expression of the enzyme was cholate inducible. The first 25 N-terminal amino acid residues of purified NADH:flavin oxidoreductase were determined, and a corresponding oligonucleotide probe was synthesized for use in cloning of the associated gene, baiH. Restriction mapping, sequence data, and RNA blot analysis suggested that the baiH gene was located on a previously described, cholate-inducible operon > or = 10 kb long. The baiH gene encoded a 72,006-Da polypeptide containing 661 amino acids. The deduced amino acid sequence of the baiH gene was homologous to that of NADH oxidase from Thermoanaerobium brockii, trimethylamine dehydrogenase from methylotrophic bacterium W3A1, Old Yellow Enzyme from Saccharomyces carlsbergensis, and the product of the baiC gene of Eubacterium sp. strain VPI 12708, located upstream from the baiH gene in the cholate-inducible operon. Alignment of these five sequences revealed potential ligands for an iron-sulfur cluster, a putative flavin adenine dinucleotide-binding domain, and two other well-conserved domains of unknown function.

Amino Acid Sequence↗
PubMed2002

Crystallographic study of the recombinant flavin-binding domain of Baker's yeast flavocytochrome b(2): comparison with the intact wild-type enzyme.

Flavocytochrome b(2) catalyzes the oxidation of L-lactate to pyruvate and the transfer of electrons to cytochrome c. The enzyme consists of a flavin-binding domain, which includes the active site for lacate oxidation, and a b(2)-cytochrome domain, required for efficient cytochrome c reduction. To better understand the structure and function of intra- and interprotein electron transfer, we have determined the crystal structure of the independently expressed flavin-binding domain of flavocytochrome b(2) to 2.50 A resolution and compared this with the structure of the intact enzyme, redetermined at 2.30 A resolution, both structures being from crystals cooled to 100 K. Whereas there is little overall difference between these structures, we do observe significant local changes near the interface region, some of which impact on amino acid side chains, such as Arg289, that have been shown previously to have an important role in catalysis. The disordered loop region found in flavocytochrome b(2) and its close homologues remain unresolved in frozen crystals of the flavin-binding domain, implying that the presence of the b(2)-cytochrome domain is not responsible for this positional disorder. The flavin-binding domain interacts poorly with cytochrome c, but we have introduced acidic residues in the interdomain interface region with the aim of enhancing cytochrome c binding. While the mutations L199E and K201E within the flavin-binding domain resulted in unimpaired lactate dehydrogenase activity, they failed to enhance electron-transfer rates with cytochrome c. This is most likely due to the disordered loop region obscuring all or part of the surface having the potential for productive interaction with cytochrome c.

Binding Sites↗
PubMed1986

Electron spin resonance studies on a flavoprotein in neutrophil plasma membranes. Redox potentials of the flavin and its participation in NADPH oxidase.

Plasma membrane fractions of stimulated and resting cells were isolated from pig blood neutrophils. The midpoint redox potential (Em) of the membrane-bound flavin was determined potentiometrically by analysis of the flavin free-radical signal by electron spin resonance (ESR) spectroscopy. In both stimulated and resting cells, a peak position of the titration curve gave an Em value of -280 mV at pH 7.0 (Em7). The flavin free radical showed an ESR spectrum at g = 2.004 with a peak to peak width of 19 G, which indicates that the redox intermediate is a neutral semiquinone. Redox titrations were anaerobically examined at 25 degrees C with NADPH in place of dithionite. Addition of NADPH to plasma membranes of stimulated cells resulted in a rapid change in potential, accompanied by the formation of the ESR signal of flavin free radical. Computer simulation of the titration points gave an ambient midpoint potential of -280 mV (Em7). In contrast, those of resting cells showed a very slow change in potential and no g = 2.00 signal formation. Power saturation behavior of the ESR signal showed a marked difference between those of stimulated and resting cells. ESR characteristics of the flavin are discussed in relation to the membrane-bound NADPH oxidase.

Animals↗
PubMed1980

Structural and electronic effects resulting from metal-flavin ligation.

The synthesis and physical properties of a model metalloflavin complex, [(10-methylisoalloxazine)-(NH3)4Ru](PF6)2 . 2H2O are reported. The structure of this stable, enantiomeric compound was elucidated by x-ray diffraction methods with a final unweighted R value of 0.054. Crystals belong to the triclinic space group P1 with unit cell dimensions: a = 9.631, b = 10.618, c = 13.216 A; alpha = 113.86, beta = 100.19, gamma = 94.12 degrees. Chelation of the metal ion to the flavin occurs at the N(5) and O(4) positions, with a short Ru-N(5) bond distance of 1.979 A. Steric and electronic factors induce a 9.9 degrees bend in the isoalloxazine ring system and a significant lengthening of the C(4a)-N(5) bond. The flavin absorption bands shift significantly toward lower energy on complexation and a new band occurs at 617 nm. These absorptions are pH-dependent and pK alpha values for the complex are 0.6 and 7.4. The spectra of this complex exhibit similarities to that of metallosemiquinone species and arguments are made that a significant amount of electron density is donated to the pi-system of the flavin. Proton NMR studies suggest enhanced electron density at the N(10) position, probably occurring through backbonding interactions. Cyclic voltametry studies are also consistent with substantial metal to ligand pi-electron donation, since it is significantly more difficult to reduce the coordinated flavin relative to the free ligand under the same conditions. Moreover, the complexed flavin accepts electrons in 1-electron rather than 2-electron steps. Spectroelectrochemical studies on the 1-electron reduced complex indicate a similarity with other M(II)-F1 species.

Chemical Phenomena↗
PubMed1993

Cerebral flavin-containing monooxygenase-mediated metabolism of antidepressants in brain: immunochemical properties and immunocytochemical localization.

Flavin-containing monooxygenase (FMO)-mediated oxidation of the model substrates N,N-dimethylaniline and methimazole, and the antidepressants imipramine and fluoxetine, was determined in rat brain microsomes. No sex-related difference was observed in the activity of the FMO-mediated metabolism of the four substrates examined. The Km values for flavin-containing monooxygenase-mediated metabolism of N,N-dimethylaniline and methimazole were 2.8 and 0.8 mM, respectively, and the Km values for the oxidation of the antidepressants imipramine and fluoxetine were 20.9 and 9.8 microM, respectively. The Vmax values for oxidation of N,N-dimethylaniline, methimazole, imipramine and fluoxetine were 340, 31, 182 and 470 nmol nicotinamide adenine dinucleotide phosphate oxidized/min/mg protein, respectively. Western immunoblot analysis using antisera to purified porcine liver FMO did not reveal any immunological cross-reactivity with male or female brain microsomal protein. Antibody to rabbit lung flavin-containing monooxygenase cross-reacted with brain microsomes as examined by Western immunoblot studies. Addition of the antibody raised against rabbit lung FMO resulted in inhibition (43% inhibition) of the FMO-mediated metabolism of imipramine. Immunocytochemical examination of rat brain sections using the above antibody revealed the preferential localization of flavin-containing monooxygenase in the neuronal cell body. The flavin-containing monooxygenase-mediated metabolism of antidepressant drugs by brain microsomes is of profound pharmacological significance.

Animals↗