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PubMed1983

Induction by barbiturates of a cytochrome P-450-dependent fatty acid monooxygenase in Bacillus megaterium: relationship between barbiturate structure and inducer activity.

In a recent communication (Narhi, L. and Fulco, A.J. [1982] J. Biol. Chem. 257, 2147-2150) we found that a soluble cytochrome P-450-dependent fatty acid monooxygenase isolated from Bacillus megaterium ATCC 14581 could be induced about 28-fold by phenobarbital. We have now examined 19 barbiturates and found that 13 significantly induce the specific monooxygenase activity. Of these, 11 are more active than phenobarbital and three (secobarbital, thiamylal and methohexital) are more than 30 times as active on a molar basis. The dialkyl barbiturates without exception show an excellent correlation between increasing lipophilicity and increasing potency as inducers as do most of the barbiturates containing an aromatic substituent. Nevertheless, it is apparent that certain structural features involving factors other than lipophilicity are also necessary for induction. Our finding that barbiturates can cause the non-substrate induction of a cytochrome P-450-dependent monooxygenase in a prokaryote represents a unique discovery that may provide a relatively simple model for apparently similar induction systems in higher animals.

Bacillus megaterium↗
PubMed1986

gamma-Aminobutyric acid (GABA)- and barbiturate-mediated 36Cl- uptake in rat brain synaptoneurosomes: evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel.

"Desensitization" of the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied using an in vitro method for measuring chloride (Cl-) permeability in brain vesicles (synaptoneurosomes). Muscimol, a GABA agonist, stimulated 36Cl- uptake in rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (EC50 7.3 +/- 0.5 microM), whereas pentobarbital stimulated 36Cl- uptake in a biphasic manner, indicated by a bell-shaped concentration-response relationship, with a maximal response at 500 microM (EC50 271 +/- 17 microM). Higher concentrations of pentobarbital led to progressively smaller stimulation of 36Cl- uptake and blocked muscimol-stimulated 36Cl- uptake. Lower concentrations of pentobarbital (100-200 microM), when added with muscimol, produced an additive effect in stimulating 36Cl- uptake, whereas even lower (subthreshold) concentrations of pentobarbital (50 microM) potentiated muscimol-stimulated 36Cl- uptake. Following continuous exposure of synaptoneurosomes (up to 20 min) to muscimol (50 microM) or pentobarbital (500 microM), the 36Cl- uptake response diminished to a new steady state level with a t1/2 of approximately 6 sec and 30 sec, respectively. The decrement in response to these agonists was dependent on both concentration and length of exposure. No decrement was observed in the ability of subthreshold concentrations of pentobarbital to enhance muscimol-stimulated 36Cl- uptake following prolonged (20 min) incubation. "Heterologous desensitization" between muscimol and pentobarbital was observed in experiments where either muscimol or pentobarbital was added to the vesicles following pretreatment with the other. These findings suggest that "desensitization" of the GABA receptor/Cl- ion channel may involve both the GABA and barbiturate recognition sites or a common effector component such as the ionophore itself.

Animals↗
PubMed1992

gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes.

Xenopus oocyte expression of the recently cloned gamma-aminobutyric acid (GABA) rho 1 receptor subunit cDNA yields a pharmacologic profile characteristic of the GABAc responses described by Johnston [Benzodiazepine/GABA Receptors and Chloride Channels. Receptor Biochemistry and Methodology (R. W. Olsen and J. C. Venter, eds), Vol. 5. Alan R. Liss, New York, 57-71 (1986)] and the responses to retinal mRNA recently reported in the Xenopus expression system [Proc. Natl. Acad. Sci. USA 88:4318-4322 (1991)]. A rationale for defining GABA rho 1 as forming a GABAc receptor is discussed.

Animals↗
PubMed1987

Cloning of the gene encoding a catalytically self-sufficient cytochrome P-450 fatty acid monooxygenase induced by barbiturates in Bacillus megaterium and its functional expression and regulation in heterologous (Escherichia coli) and homologous (Bacillus megaterium) hosts.

In a previous publication (Narhi, L. O., and Fulco, A. J. (1986) J. Biol. Chem. 261, 7160-7169) we described the characterization of a 119,000-dalton P-450 cytochrome that is strongly induced by barbiturates in Bacillus megaterium. In the presence of NADPH and O2, this single polypeptide can catalyze the hydroxylation of long-chain fatty acids without the aid of any other protein. The gene encoding this unique monooxygenase (cytochrome P-450BM-3) has now been cloned by an immunochemical screening technique. The Escherichia coli clone harboring the recombinant plasmid produces a 119,000-dalton protein that appears to be electrophoretically and immunochemically identical to the B. megaterium enzyme and contains the same N-terminal amino acid sequence. The recombinant DNA product also exhibits the characteristic cytochrome P-450 spectrum and is fully functional as a fatty acid monooxygenase. In E. coli, the synthesis of P-450BM-3 is directed by its own promoter included in the DNA insert and proceeds constitutively at a very high rate but is not stimulated by pentobarbital. However, when the cloned P-450BM-3 gene, either intact or in a truncated form, is introduced back into B. megaterium via an E. coli/Bacillus subtilis shuttle vector, its expression is constitutively repressed but is induced by pentobarbital. This finding demonstrates that the regulatory region of the P-450BM-3 gene that responds to barbiturates is included in the cloned DNA. The evidence also indicates that pentobarbital cannot directly act on the gene to cause induction but presumably interacts with another component such as a repressor molecule that is present in B. megaterium but is absent in the E. coli clone.

Bacillus megaterium↗
PubMed1999

Clinical trials in head injury.

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Arachidonic Acid↗
PubMed1997

Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to the manufacture of more designer drugs. Production of substituted phenethylamines was facilitated by the drug makers' cook book, 'PIHKAL' (Phenethylamines I Have Known And Loved) by Dr Alexander Shulgin and Ann Shulgin, and production of substituted tryptamines is promised in their next book, TIHKAL. Looking to the future, laboratories will need to ensure that they can detect and quantitate an ever-increasing number of drugs and related substances. The question of confidence in results of drugs of abuse testing raised in 1993 by Watson has assumed even greater importance as a result of attention focused on the OJ Simpson trial in Los Angeles. Toxicological investigations are likely to be challenged more frequently in the future. Even if analyses have been performed by GC-MS, there is a need to establish the level of match between the spectrum of the unknown substance and a library spectrum which is considered acceptable for legal purposes. It will also be essential to ensure that computer libraries contain spectra for all substances likely to be encountered in drugs of abuse screening.

Barbiturates↗
PubMed1990

Physiological modulation of the GABA receptor by convulsant and anticonvulsant barbiturates in cultured rat hippocampal neurons.

The actions of convulsant and sedative barbiturates on responses to gamma-aminobutyric acid (GABA) application and on inhibitory postsynaptic currents were compared using voltage-clamp techniques in cultured rat hippocampal neurons. The convulsant barbiturates, 5-ethyl-5-(3-methylbut-2-enyl) barbituric acid (3M2B), and (+)-5-ethyl-5-(1,3-dimethylbutyl) barbituric acid [+)-DMBB), and the sedative barbiturate, 5-ethyl-5-(3-methylbutyl) barbituric acid (3MB), all potentiated GABA-mediated chloride currents. In addition, these compounds prolonged the duration of GABAergic inhibitory postsynaptic currents. The similarity between the action of convulsant and sedative barbiturates suggests that the convulsant activity of 3M2B and (+)-DMBB are not mediated by their actions at GABAergic synapses.

Animals↗
PubMed1963

LICHEN PLANUS.

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Adrenal Cortex Hormones↗