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PubMed1988

Action of polychlorocycloalkane insecticides on binding of [35S]t-butylbicyclophosphorothionate to Torpedo electric organ membranes and stereospecificity of the binding site.

Binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to Torpedo electric organ membranes was characterized. A dose- and pH-dependent binding (100.8 pmol/mg protein) was detected with a single affinity (Kd of 0.9 microM) in the presence of 150 mM KCl at pH 6.8. Other anions such as Br- and I- also increased binding affinity, but to a lower degree than Cl-, which increased the affinity by two- to threefold. In presence of 150 mM KCl, [35S]TBPS binding was inhibited noncompetitively by Zn2+ and by 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) (IC50 of 9 microM). The gamma-isomer of hexachlorocyclohexane (BHC) was much more potent in inhibiting this [35S]TBPS binding and the inhibition was competitive (Ki = 40 nM). Like binding of [35S]TBPS to the gamma-aminobutyric acid (GABA) receptor, its binding to Torpedo membranes was inhibited by pentobarbital, mephobarbital, and hexobarbital (IC50 of 85, 225, and 300 microM), respectively), but not by phenobarbital. Binding was not inhibited by diazepam, GABA, bicuculline, or avermectin B1a, ligands that bind to the GABAA receptor. [35S]TBPS binding was inhibited by BHC isomers with the following decreasing order of potency alpha = gamma greater than sigma greater than beta, and by cyclodiene insecticides. Endrin was more potent than dieldrin, but endosulfan I and II had similar effects. The data suggest that the binding site for polychlorocycloalkane insecticides on this protein is much less stereoselective than that of the Cl- channel of the GABAA receptor. Also, even though this Torpedo protein has higher affinity for insecticides, such as gamma-BHC, than does the GABAA receptor, it is the latter whose specificity correlates best with polychlorocycloalkane toxicity. Nevertheless, because of its high affinity for gamma-BHC such a protein in muscles or brain may be an important target for the action of this insecticide.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1994

Simultaneous determination of antiepileptic drugs and their metabolites, including chiral compounds, via beta-cyclodextrin inclusion complexes by a column-switching chromatographic technique.

Using beta-cyclodextrin as a mobile-phase additive, a column-switching chromatographic system equipped with two 25-mm short ODS cartridge columns and two UV detectors was successfully employed for the simultaneous determination of some antiepileptic drugs and their metabolites, including chiral compounds, in human serum. The compounds examined were phenobarbital, zonisamide, phenytoin and its metabolites, S- and R-5-(p-hydroxyphenyl)-5-phenylhydantoin, R- and S-mephobarbital, carbamazepine and its main metabolites, 10,11-dihydro-10-11-epoxycarbamazepine and trans-10,11-dihydroxy-10,11-dihydrocarbamazepine (as a racemate), and allobarbital (as an internal standard).

Anticonvulsants↗

PubMed1990

Displacement chromatography on cyclodextrin-silicas. III. Enantiomer separations.

The feasibility of preparative enantiomer separations by displacement chromatography on analytical-scale beta-cyclodextrin-silica columns, operated in the reversed-phase mode, was demonstrated using the enantiomers of mephobarbital, hexobarbital, dansylleucine, dansylvaline and dansylphenylalanine as model solutes. The method development scheme (which relies on the determination of the elution-mode retention behavior and the adsorption isotherms of the solutes and the candidate displacers) described in Parts I and II can be used to select the appropriate displacers and the conditions leading to a successful displacement chromatographic separation. The importance of the displacer (both type and concentration) to the success of the displacement chromatographic separation is demonstrated.

Amino Acids↗

PubMed1994

Gender differences in human pharmacokinetics and pharmacodynamics.

Gender differences in pharmacokinetics and pharmacodynamics have long been recognized in animals. In humans, however, little attention has been paid to this field despite at least theoretical reasons to believe that gender may be an important variable in the processes of absorption, distribution, metabolism, and excretion. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, amount of drug binding proteins, gender-specific cytochrome P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and renal blood flow are several factors that may contribute to sex-related differences in pharmacokinetics. Clinical investigations have documented greater absorption and subsequent incorporation of iron into erythrocytes, and higher bioavailability of ethanol in females. Women have been shown to have a slower metabolism of mephobarbital and propranolol but an increased biotransformation of methylprednisolone, all three of which are metabolized by enzymes of the cytochrome P450 system. Lastly, the renal excretion of amantadine was inhibited significantly by quinidine and quinine in men but not in women. While gender-specific pharmacodynamic data are meager, evidence also supports the existence of sex-related differences. Women appear to be more prone to develop torsades de points from drugs such as quinidine and procainamide than men. A dimorphism in insulin sensitivity has been demonstrated with males having an enhanced response compared to females. Pharmacokinetic and pharmacodynamic sex-related differences exist and are complex. Future research efforts should be designed to provide more gender-specific information on drug disposition and clinical effect.

Adolescent↗

PubMed1997

Clinical and toxicological findings in two young siblings and autopsy findings in one sibling with multiple hospital admissions resulting in death. Evidence suggesting Munchausen syndrome by proxy.

A 15-month-old girl underwent several emergency department (ED) visits and two admissions for parent-reported histories of ingestions, apnea, and seizures. She was initially admitted following reports of several unusual episodes of syncope accompanied by convulsive movements and was discharged on mephobarbital with a diagnosis of atypical seizure disorder. The day after discharge, she was brought to the ED in cardiopulmonary arrest and was resuscitated after a prolonged period. She was declared brain dead 2 days later. Ante- and postmortem toxicology produced several inconclusive findings, none of which explained death. Autopsy findings, including neuropathology, failed to demonstrate any significant disease processes. Approximately 3 months later, a 4-month-old female sibling was brought to the ED with a parent-reported history of apnea and seizures similar to the deceased child. A stool specimen obtained 2 days after admission contained numerous tiny seeds, which were found by gas chromatography-mass spectrometry analysis to contain lorazepam and temazepam. The role of these benzodiazepines in the apnea episodes in this infant was unknown, but the presence of the seeds in such a young infant coupled with the parent's aberrant behavior, led to the tentative diagnosis of Munchausen syndrome by proxy. This diagnosis was strengthened when results from these studies persuaded legal authorities to remove the surviving sibling from the parents, resulting in an asymptomatic recovery.

Anti-Anxiety Agents↗

PubMed2004

Key structural features of ligands for activation of human pregnane X receptor.

The ligand-binding domain of human pregnane X receptor (hPXR) is highly hydrophobic and flexible, allowing promiscuity in accepting structurally diverse ligands. However, little information is available regarding the critical substituents of compounds involved in the activation of hPXR. The aim of this study was to determine the structure-activity relationships for hPXR-mediated transactivation by barbiturates, hydantoins, and macrolide antibiotics. Most of the barbiturates studied (mephobarbital, pentobarbital, phenobarbital, etc.) activated hPXR. However, barbital, which has a low hydrophobic moiety at the 5-position, and primidone, which has no carbonyl moiety at the 2-position, did not activate hPXR. Therefore, a hydrophobic moiety at the 5-position and a hydrogen-bond acceptor being sufficiently separated from the phenyl-ring are responsible for activation of hPXR by barbiturates. In the case of hydantoins, only mephenytoin and ethotoin, which have an alkylchain at the R1-position, strongly activated hPXR at 300 microM. Phenytoin and 5-(4-methylphenyl)-5-phenylhydantoin, which contain a phenyl or methylphenyl group at both R2- and R3-positions, also activated hPXR, whereas 5-(4-hydroxyphenyl)-5-phenylhydantoin did not activate the receptor. These results suggest that the presence of an alkyl-chain at the R1-position and the presence of bulky and hydrophobic moieties at both R2- and R3-positions are important factors for activation of hPXR by hydantoins. In the case of macrolide antibiotics, troleandomycin, but not oleandomycin, showed significant activation of hPXR. Therefore, triacetate esterification of oleandomycin might increase the hydrophobicity and enhance the activation of hPXR. These findings suggest that hydrophobicity of the ligand and adequate distance between the hydrogen-bond acceptor and the hydrophobic group are important for hPXR activation.

Anti-Bacterial Agents↗

PubMed1994

Effect of anesthetic and convulsant barbiturates on N-methyl-D-aspartate receptor-mediated calcium flux in brain membrane vesicles.

The effects of anesthetic and convulsant barbiturates on brain N-methyl-D-aspartate (NMDA) receptor function were examined in a cell-free membrane vesicle preparation from mouse hippocampus. Increases in intracellular free calcium concentrations (Cai) were determined using a fluorescent dye, Indo-1, after stimulation with the NMDA receptor agonist, L-glutamate. Anesthetic barbiturates inhibited NMDA responses in a concentration-dependent manner with a rank order of potency of secobarbital > amobarbital > pentobarbital > mephobarbital = phenobarbital >> barbital. However, the IC50 values for these barbiturates were larger than probable blood anesthetic concentrations. Barbiturates with both anesthetic and convulsant effects in mice [optical isomers of pentobarbital and secobarbital, 5-(2-cyclohexylideneethyl)-5-ethylbarbituric acid and (+/-)-dimethylbutylbarbituric acid] also reduced NMDA responses. Inhibition of NMDA responses by racemic pentobarbital or isomers of pentobarbital was noncompetitive. Resting Cai was altered by all barbiturates tested except secobarbital and barbital, but not in a consistent manner, suggesting that the effect of barbiturates on resting Cai is not related either to their effects on NMDA receptor responses or to their behavioral effects. These results show that anesthetic and convulsant barbiturates inhibit NMDA responses, but their anesthetic and convulsant activities may be primarily due to their effects on other brain targets.

Animals↗

PubMed1976

Rapid micromethod for measuring anticonvulsant drugs in serum by high-performance liquid chromatography.

We describe an assay system for measuring phenobarbital, diphenylhydantoin, primidone, ethosuximide, and carbamazepine in 25 mul of serum. The procedure involves precipitation of proteins with an acetonitrile solution containing cyheptamide as an internal standard, and reverse-phase chromatography on a 4 mm X 30 cm column containing "muBondapak C18." The anticonvulsants are eluted with an equivolume mixture of potassium phosphate buffer (10 mmol/liter, pH 8.0) and acetonitrile at a flow rate of 0.8 ml/min, detected by their absorbance at 200 nm, and quantitated by measuring peak areas. When measurement of primidone is not required, a 254-nm detector may be used. Each analysis requires 10 min. Optimum column temperature has been found to decrease with use. Analytical recoveries for the five drugs varied from 92% to 102% with good precision (coefficients of variation between 2.8% and 9.2% for therapeutic and toxic concentrations). The results obtained with this method compare favorably with results obtained by gas-liquid chromatography (correlation coefficients between 0.77 and 0.98). In over 1300 patients' samples analyzed to date, the only drugs known to have interfered with the assay are gentamicin, diazoxide, and mephobarbital.

Anticonvulsants↗

PubMed1976

Ultramicro gas-chromatographic analysis for anticonvulsants, with use of a nitrogen-selective detector.

We describe a procedure for determining phenobarbital, primidone, and diphenylhydantoin simultaneously in 50-mul volumes of serum by use of gas chromatography and a detector with heightened sensitivity and selectivity for nitrogenous compounds. The drugs, together with an internal standard, 5-allyl-5-phenyl barbituric acid, are extracted from serum by the procedure of MacGee [Anal. Chem. 42, 421 (1970)]. The drugs are converted to their methyl derivatives by a modification of the procedure of Greeley [Clin. Chem. 20, 192 (1974)] and then analyzed on a column containing 3% OV-1, with a temperature program, and detected by a nitrogen-selective detector. The method is reproducible to about 7%. Sensitivities of 0.5 mg/liter for 50-mul serum samples are attained routinely. Mephobarbital interferes with the analysis because methylation yields the same product as methylated phenobarbital. Total analysis time for a single sample is 15 min.

Chromatography, Gas↗

PubMed1991

[A case of phenytoin intoxication induced by hypothyroidism].

A 42-year-old woman who presented phenytoin intoxication induced by acute hypothyroidism was reported. She had a 29-year history of hypothyroidism and a 18-year history of epilepsy. She was treated with phenytoin (PHT) 100 mg, mephobarbital (MPB) 200 mg, valproic acid (VPA) 400 mg and thyroid powder 100 mg daily for 2 years. She had no medical problem until she noticed gait disturbance and diplopia which appeared 1 month after sudden withdrawal of thyroid powder. On admission, she was somnolent and somewhat disoriented. She had nystagmus in horizontal direction of gaze. Her speech was slurred and she could not sit nor stand due to trunkal ataxia. There was prominent intentional tremor in finger-nose test and heel-shin test showed severe ataxia. Blood cell count and blood chemistry examinations were normal. Serum PHT, phenobarbital (PB) levels were elevated as to 26.4, 36.4 micrograms/ml, respectively. VPA level was low. The endocrinological examinations revealed primary hypothyroidism. EEG showed generalized slow background, but cranial MRI, EMG, SEP and ECG were normal. Thyroxine (T4) administration was started soon, and in the course of thyroid hormone replacement, her cerebellar symptoms gradually improved and serum PHT level decreased even to the subtherapeutical level with the same amount of antiepileptic drugs treatment. By the 40th day of admission, thyroid function became normal and cerebellar signs disappeared, however, she needed 200 mg PHT daily to obtain good control of epilepsy. Cerebellar symptoms of this patient were thought to be PHT intoxication rather than ataxia caused by hypothyroidism itself from the viewpoint of clinical manifestations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1986

Anesthetic and convulsant barbiturates alter gamma-aminobutyric acid-stimulated chloride flux across brain membranes.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, increases membrane chloride conductance. Previously, the authors reported that GABA increases 36Cl- uptake by membrane vesicles (microsacs) prepared from mouse brain. In the present study, we examined the actions of barbiturates on basal and GABA-stimulated chloride influx by brain vesicles. The anesthetic barbiturates pentobarbital, phenobarbital, mephobarbital, amobarbital, hexobarbital and R-(-)-1-methyl-5-phenyl-5-propyl barbiturate enhanced GABA-dependent chloride flux. Barbiturate enhancement of GABA action was seen at concentrations that are subanesthetic in vivo (e.g., 10 microM pentobarbital was effective). Pentobarbital was about 10 times more potent than pentobarbital, suggesting that chloride flux is related to the sedative rather than anticonvulsant actions of barbiturates. Pentobarbital (1 mM) prevented the antagonism of GABA-stimulated 36Cl- produced by picrotoxinin. The barbiturates generally produced no change in GABA-independent flux, although large concentrations of pentobarbital or hexobarbital produced a slight enhancement of chloride flux in the absence of GABA. The convulsant barbiturate S-(+)-1-methyl-5-phenyl-5-propyl barbiturate inhibited GABA-stimulated chloride flux, an action opposite to that of its anesthetic enantiomer. These experiments provide evidence for a functional coupling among GABA and barbiturate receptors and the chloride ionophore and suggest that the GABA-activated chloride channel is a site of action for intoxicant-anesthetic and convulsant barbiturates.

Animals↗

PubMed1987

Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes.

The in vivo metabolism in humans of the anticonvulsant mephenytoin exhibits stereoselectivity as well as genetic polymorphism of the 4-hydroxylation pathway. The characteristics of the involved cytochrome P-450 isozyme are, however, not known completely. Accordingly, the ability of human liver microsomes to metabolize mephenytoin and its enantiomers was investigated in vitro, and the ability of related anticonvulsants and other compounds to inhibit 4-hydroxylation was studied. Marked stereoselectivity was observed in the conversion of S-mephenytoin to its 4-hydroxy metabolite, but N-demethylation was essentially similar for both enantiomers. The intrinsic clearance (Vmax/Km) for 4-hydroxymephenytoin formation showed an almost 10-fold range in five livers and was 150- to 1000-fold greater than that for N-demethylation. Competitive inhibition of 4-hydroxylation was observed with ethotoin, mephobarbital, methsuximide and phensuximide, but not other commonly used anticonvulsants such as ethosuximide, phenobarbital, phenytoin and primidone. However, synthetic N-alkyl analogs of the latter compounds were found to be inhibitory. An aryl residue alpha to the carbonyl carbon of an N-alkyl lactam in a 5- or 6-membered ring, therefore, appears to be a minimal requirement for strong interaction with the 4-hydroxylase. Warfarin, but not diazepam, ketoconazole or iodochlorohydroxyquin, were also competitive inhibitors, but at much higher concentrations than the anticonvulsants. Competitive inhibition at concentrations similar to the Km of 4-hydroxymephenytoin formation (30-350 microM) may indicate that the isozyme is involved in the metabolism of the substrates under consideration and, therefore, their in vivo metabolism may be regulated to some extent by the same genetic factor(s) that determine mephenytoin's biotransformation.

Anticonvulsants↗

PubMed1988

Isocratic liquid chromatographic determination of theophylline, acetaminophen, chloramphenicol, caffeine, anticonvulsants, and barbiturates in serum.

An isocratic reverse-phase high-performance liquid chromatographic system is described for resolving theophylline, acetaminophen, caffeine, chloramphenicol, ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine within 7 min. A procedure for routinely measuring these drugs in serum is validated and has been extended to include the quantification of N-desmethylmethsuximide, barbital, amobarbital, secobarbital, pentobarbital, mephobarbital, and thiopental. A 250 x 4.6 mm column packed with trimethylsilyl (C-1)-coated 5-microns particles is used. The mobile phase is phosphate buffer (10 mmol/L, pH 6.3):methanol:acetonitrile, 65:17.5:17.5. A common solvent extraction procedure is used for all of these drugs. The extractant is chloroform:isopropanol (95:5), containing three internal standards: 3-isobutyl-l-methylxanthine (IMX), tolybarb, and methsuximide. Theophylline, acetaminophen, caffeine, and chloramphenicol are quantified at 273 nm with IMX as the internal standard. With two exceptions, the rest of the drugs are quantified at 204 nm using tolybarb as the internal standard; ethosuximide is quantified at 204 nm using methsuximide as the internal standard, and thiopental is quantified at 285 nm using IMX as the internal standard.

Acetaminophen↗

PubMed1980

Measurement of sodium valproate in serum by direct-insertion chemical-ionization/mass spectrometry.

To quantitatively determine sodium valproate, we use a stable isotope-labeled internal standard and chemical-ionization/mass spectrometry, without prior chromatographic separation. The technique is rapid, simple, sensitive, and provides for the routine analysis of 100 microL of serum with good within-day and day-to-day precision. The technique also allows for the simultaneous determination of phenobarbital, mephobarbital, carbamazepine, primidone, and phenytoin.

Carbamazepine↗

PubMed1982

Drug quality assessment methods. I. Gas-liquid chromatographic assay and identification of seven barbiturates.

A gas-liquid chromatographic (GLC) procedure has been developed for the assay and identification of amobarbital, butabarbital, heptabarbital, mephobarbital, pentobarbital, phenobarbital, and secobarbital in single component capsule, elixir, injectable, suppository, and tablet formulations. After extraction into chloroform from an acidified aqueous mixture of the product, the drug is eluted isothermally from a methylphenylsilicone GLC column at 210 or 240 degrees C and quantitated relative to thiamylal internal standard. Results were in good agreement with those obtained using pharmacopeial assay methods. The method is suitable for the rapid assessment of commercial formulations.

Barbiturates↗

PubMed1981

[Changes in serum levels of alkaline phosphatase, calcium, and inorganic phosphate following antiepileptic therapy (author's transl)].

Relationship of antiepileptics to serum alkaline phosphatase (ALP), serum calcium (Ca) and inorganic phosphate (P) were studied in 172 epileptic patients treated with antiepileptics for clarifying the related factors to produce osteomalacia following antiepileptics administration. Laboratory findings of ALP, Ca, and P were compared with normal value and determined as abnormal by exceeding the normal limit (mean +2SD (ALP), mean-2SD (Ca, P)). The following results were obtained: 1) In the 172 patients, 20 cases (11.6%) showed abnormal value of ALP, 12 cases (7.0%) of Ca and 41 cases (23.8%) of P (Single abnormal groups). On the other hand, 47 cases (27.3%) were found abnormal in two or three of ALP, Ca and P (Combined abnormal group). The rest 52 cases (30.2%) of the patients showed all normal value (Normal group). 2) Abnormal value of ALP and/or Ca were observed mostly before 20 years of age. The patients with abnormal P were more distributed in age than others. 3) The earlier and/or the longer administration of antiepileptics is prone to produce the more abnormal value. 4) Acetazolamide, metharbital, primidone, carbamazepine and mephobarbital were more used in combined group than in normal group, and polypharmaceutical use of these antiepileptics was supposed to be related to the abnormality of ALP, Ca and P. There was no different use of diphenyl-hydantoin and phenobarbital in frequency and amount between combined group and normal group. 5) Mental retardation and epileptic personality changes were observed more frequently in combined abnormal group than in normal group. 6) No significant relations were observed between clinical seizure types, seizure frequencies and abnormal laboratory findings.

Adolescent↗

PubMed1995

Application of micellar electrokinetic capillary chromatography to forensic analysis of barbiturates in biological fluids.

Micellar electrokinetic capillary chromatography (MECC) is a form of capillary zone electrophoresis. Addition of a surfactant produces micelles in an aqueous/organic buffer. Separation of drugs is obtained via differences in the electrophoretic mobilities of the analytes within the capillary, resulting from their electrophoretic velocity and the electroosmotic flow of the buffer in a given electric field. The migration order is determined by the differential partitioning of the drugs between the micelles and the aqueous/organic phase. Barbiturates were extracted from various biological fluids at pH 4.5 with TOXI-TUBES B. MECC analyses were performed using a Waters Quanta 4000 Capillary Electrophoretic System with a 745 Data Module with a 75 microns x 60 cm capillary and an aqueous/organic buffer of 85% 10 mM borate, 10 mM phosphate, 100 mM sodium dodecyl sulfate and 15% acetonitrile at a pH of 8.5 with a voltage of 20 kV using ultraviolet absorption detection at 214 nm. Migration times were: phenobarbital, 7.78 min.; butalbital, 8.01 min.; butabarbital, 8.23 min.; mephobarbital (internal standard), 8.88 min.; amobarbital, 9.41 min.; pentobarbital, 10.03 min. and secobarbital, 10.79 min. Correlation coefficients (r) between peak areas and concentration ranges of 3 to 60 micrograms/mL were from 0.964 to 0.999. Coefficients of variation (CV) ranged from 2.6 to 8.6% between days and 2.3 to 9.8% within day. Application of this methodology to four forensic cases of butalbital intoxication detected concentrations of 0.7 to 12.7 micrograms/mL in blood; 0.8 to 1.9 micrograms/mL in vitreous humor and 1.5 to 7.6 micrograms/mL in urine. MECC is applicable to forensic analysis of barbiturates extracted from biological fluids.

Barbiturates↗

PubMed1993

Inhibition by barbiturates of the binding of Bm3R1 repressor to its operator site on the barbiturate-inducible cytochrome P450BM-3 gene of Bacillus megaterium.

In our previous publication (Shaw, G.-C., and Fulco, A. J. (1992) J. Biol. Chem. 267, 5515-5526), we reported that Bm3R1, a protein encoded in an open reading frame just upstream from the cytochrome P450BM-3 gene, is a repressor critically involved in the barbiturate-inducible expression of this gene in Bacillus megaterium. We now describe the purification of the Bm3R1 protein from an overproducing Escherichia coli strain harboring a bm3R1 gene-carrying plasmid and report the effect of barbiturate inducers on the interaction of Bm3R1 with a fragment of B. megaterium DNA containing the bicistronic operator and promoter sequences. Gel filtration analysis revealed that, under our experimental conditions, most of the Bm3R1 protein exists in highly aggregated forms. Gel mobility shift assays showed that Bm3R1 protein bound specifically to a segment of DNA containing the promoter-operator region of the bm3R1 gene while DNase I footprinting experiments established that Bm3R1 protected a region of DNA that covers and flanks the palindromic operator sequence. The interaction between Bm3R1 repressor and its operator, in vitro, was strongly inhibited by the addition of 2 mM pentobarbital or 2 mM methohexital (strong in vivo inducers of P450BM-3) but not by the same concentration of phenobarbital (a relatively weak inducer) or by mephobarbital (a non-inducer). A detailed comparison of pentobarbital and methohexital at concentrations lower than 2 mM indicated that methohexital was 5-10 times more effective as an inhibitor of Bm3R1 binding in vitro, as compared with its 7-fold greater inducer potency in vivo. The observation that the in vitro inhibition effects of barbiturates on the interaction of Bm3R1 repressor and its operator correlate strongly with their in vivo potency as inducers of cytochrome P450BM-3 suggests a mechanism for the induction process. It seems plausible that the barbiturate inducers might bear a conformational resemblance to and mimic the mode of action of an as yet unidentified endogenous inducer(s) in B. megaterium that functions by releasing the binding of Bm3R1 repressor from its operator site.

Bacillus megaterium↗