GLUT1-deficiency: barbiturates potentiate haploinsufficiency in vitro.

Klepper J, Fischbarg J, Vera JC, Wang D, De Vivo DC.

Division of Pediatric Neurology, Columbia University, New York, NY 10032, USA.

Barbiturates are known to inhibit glucose transport mediated by the facilitative sugar transporter GLUTI. We have studied such inhibition in children with GLUT1-deficiency. Zero-trans influx of 14C-labeled 3-O-methyl glucose (3OMG) into erythrocytes of patients (n = 3) was 35% of controls (n = 6). Preincubation with 10 mM phenobarbital or pentobarbital reduced patients' 30MG influx to 17%. In patients and controls, preincubation with barbiturates significantly decreased Vmax in a dose-dependent manner (for pentobarbital, IC50 = 0.84 mM, patient 2). The apparent Km in individuals remained largely unchanged. Three-OMG influx without preincubation resulted in a stronger inhibition at lower barbiturate concentrations. The patients' data are discussed in the light of individual missense mutations (patient 1: R126L and K256V; patient 2: T310I; patient 3: S66F) in the GLUTI gene. In conclusion, in controls and patients with GLUT1-deficiency barbiturates interact with GLUT1, lowering its intrinsic activity. The use of barbiturates in this condition for anesthesia or as anticonvulsants could therefore potentially aggravate the existing glucose transport defect and may put these patients at increased risk.

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The effect of implementation of guidelines for the management of severe head injury on patient treatment and outcome.

Vukic M, Negovetic L, Kovac D, Ghajar J, Glavic Z, Gopcevic A.

Department of Neurosurgery, Sisters of Mercy University Hospital, Zagreb, Croatia.

The authors retrospectively analysed two groups of consecutive patients who were similarly matched for brain injury severity. From a total of 39 severe head injury patients, 23 were treated according to the Guidelines for the Management of Severe Head Injury with intracranial pressure (ICP) monitoring ("Guidelines group"). Such an approach allowed the maintenance of ICP within normal values, especially in patients with intraventricular ICP monitoring allowing the release of cerebrospinal fluid (CSF) from the ventricular system. In the Guidelines group only two patients were administered barbiturates, after all other means of ICP lowering had been exhausted. The second group consisted of 16 patients who were not monitored for ICP ("non-Guidelines group"). In this group, management consisted of the prophylactic administration of barbiturates, high dose osmotic diuretics and hyperventilation usually at levels below 25 mm Hg. In the Guidelines group the mortality rate was 30% compared to 44% in the non-Guidelines group. Almost twice as many patients achieved a "favourable" (good recovery and moderate disability) outcome (49%) compared to the non-Guidelines treated patients (25%). Furthermore, there was a 32% decrease in severe neurological disabilities in those patients in the Guidelines group. It seems that the implementation of "Guidelines" in the treatment of severe head injury, based on the result of our clinical study, reduces death and disability rates in patients with severe head injury. The administration of therapy based on the "Guidelines principles" and monitoring of ICP, can minimise the application of those therapeutic modalities (barbiturate coma and prolonged hyperventilation) which, in addition to favourable effects, may also have harmful effects on patients with severe head injury.

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Barbiturates inhibit progesterone synthesis in cultured Leydig tumor cells and human granulosa cells.

Gocze PM, Szabo I, Porpaczy Z, Freeman DA.

Department of Obstetrics and Gynecology, Medical University of Pecs, Hungary.

Screening drugs used in obstetrical practice for effects on steroid hormone synthesis revealed that phenobarbital inhibited progesterone synthesis in MA-10 Leydig tumor cells. The inhibition was apparently a drug class effect since it could be reproduced by other barbiturates. Barbiturate blockade was reversible and could be bypassed in the MA-10 cells by using 22-hydroxycholesterol. Human granulosa cell progesterone synthesis was also inhibited in a dose dependent fashion by phenobarbital, secobarbital and barbituric acid. Significant inhibition occurred in dose ranges that would be therapeutic for treating epilepsy. From these data we conclude that barbiturates block steroidogenesis by inhibiting cholesterol transport to the cholesterol side chain cleavage enzyme.

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In vivo roles of Bm3R1 repressor in the barbiturate-mediated induction of the cytochrome P450 genes (P450(BM-3) and P450(BM-)1) of Bacillus megaterium.

Liang Q, Chen L, Fulco AJ.

Department of Biological Chemistry, School of Medicine, University of California, 4042A Young Hall, 607 Circle Drive South, Los Angeles, CA 90095-1569, USA.

We previously showed [Q. Liang, A.J. Fulco, J. Biol. Chem., 270 (1995) 18606-18614) that the binding of Bm3R1 repressor to Barbie box elements and operator sites in the 5'-flanking regions of the P450BM-3 and P450BM-1 (CYP102 and CYP106) genes in Bacillus megaterium was a critical factor in their regulation at the level of transcription. We now describe experiments that delineate specific roles for Bm3R1 in the barbiturate-mediated induction of these genes. We directly demonstrate the interaction of Bm3R1 with Barbie box and operator sequences and show that high in vivo levels of Bm3R1 prevent putative positive factors from binding to Barbie box elements, strongly inhibit the expression of the P450 genes, prolong the lag phase of growth in Bacillus megaterium cultures and increase the sensitivity of the cells to the growth-inhibitory effects of barbiturates. Finally, our data suggest that there may be two forms of Bm3R1, either of which can interact with OIII, the bicistronic operator sequence. Copyright 1998 Elsevier Science B.V.

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