A convulsant, 3-mercaptopropionic acid,decreases the level of GABA and GAD in rat pancreatic islets and brain

To investigate the properties of the gamma-aminobutyric acid (GABA) synthesizing enzyme, glutamate decarboxylase (GAD), in the brain and the pancreatic islets of the rat, GABA concentration in the brain and the pancreatic islets was measured after intraperitoneal administration of 3-mercaptopropionic acid (3-MP) at 25 mg/kg. 60 min after the administration of 3-MP, GABA concentration in the hypothalamus, the superior colliculus and the hippocampus of the brain decreased by 20–30% and in the pancreatic islets by 35%. The concentration in the pancreatic acini did not change. Western blotting showed that GAD activity in the pancreatic islets decreased after administration of 3-MP compared to the control. The activity of GAD in the pancreatic islets as well as brain can be modified by a convulsant, in this case 3-MP. These results suggest the properties of GAD may be similar in the pancreatic islets and brain.     

A survey of 3-dehydroretinal as a visual pigment chromophore in various species of crayfish and other freshwater crustaceans

Summary 3-Dehydroretinal (vitamin A₂ aldehyde) was found in the eyes of three species among 10 species of freshwater crayfish examined. Since dark-adapted eyes contained the 11-cis form of 3-dehydroretinal, this compound must be the chromophore of the visual pigment. 3-Dehydroretinal always coexisted with retinal (vitamin A₁ aldehyde), indicating the presence of a rhodopsin-porphyropsin visual pigment system.     

Inhibition of cholesterol synthesis ex vivo and in vivo by fluvastatin,a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase

The inhibitory effect of fluvastatin sodium (fluvastatin), a new type of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A inhibitor, on de novo cholesterol synthesis was investigated and compared with that of pravastatin. Fluvastatin at a concentration of 12.5 mg/kg inhibited sterol synthesis ex vivo from [¹⁴C]acetate in rat liver and ileum by 97–99% with respect to the control, while the inhibition in kidney was 55%. The inhibition by fluvastatin in the liver and ileum persisted for approximately 9 h after administration. Significant differences between fluvastatin also had an inhibitory effect on cholesterol synthesis in vivo in various tissues of rats given [¹⁴C]acetate intraperitoneally. Sterol synthesis in the liver, ileum and kidney was inhibited by over 95% 3 h after administration of 6.25 mg/kg of fluvastatin. Significant differences between fluvastatin and pravastatin were found in the liver and ileum. Fluvastatin was more potent than pravastatin in inhibiting both ex vivo and in vivo sterol synthesis in the ileum (but not in kidney) and liver.     

Genetic factors in neurotoxicology and neuropharmacology: A critical evaluation of the use of genetics as a research tool

Animals have evolved a detoxication system to enable them to survive in a hostile chemical environment in which foods contain many non-nutrient chemicals. Detoxication depends on enzymes which are often genetically polymorphic. As a result, inter-individual variation is common, and in humans several Mendelian loci have been identified. However, most variation in response is probably due to the action of several genes. Genetic variation in response to the neurotoxin MPTP and to chemically and physically-induced seizures is reviewed. In the former case, differences between pigmented and white mouse strains have been noted which are consistent with the hypothesis that humans are more sensitive than mice or rats because of the presence of melanin in human brains. However, variation in sensitivity probably also depends on other genes. In the case of audiogenic seizures, a single locus has been identified and mapped, but its relationship with seizures induced by other agents is not clear. Genetic variation in response to alcohol is also discussed. The failure of most toxicologists to consider genetic variation as a potentially confounding variable, and as a powerful research tool, is discussed critically in relation to non-repeatability of research on the neurotoxic effects of lead, and in relation to the genetic variation in MPTP, seizures, and alcohol response already noted. It seems clear that genetic methods provide a powerful research tool which is largely being ignored by toxicologists.     

Electrophoretic changes of serum and virus particles type ‘C’ and ‘A’ in a plasmocytoma of Balb/c mice

Zusammenfassung Untersuchungen an einem Plasmocytom von BALB/c-Mäusen ergaben keine Beziehungen zwischen dem Vorkommen von virusähnlichen Partikeln des Typus «A» und «C» und der Sekretion von Immunoglobulin.

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We are indebted to Mrs.U. Roost for her excellent technical assistance.     

A common ancestor for a subunit in the mitochondrial proton-translocating NADH:ubiquinone oxidoreductase (complex I) and short-chain dehydrogenases/reductases

The proton-translocating NADH:ubiquinone oxidoreductase or complex I is located in the inner membranes of mitochondria, where it catalyzes the transfer of electrons from NADH to ubiquinone. Here we report that one of the subunits in complex I is homologous to short-chain dehydrogenases and reductases, a family of enzymes with diverse activities that include metabolizing steroids, prostaglandins and nucleotide sugars. We discovered that a subunit of complex I in human, cow, Neurospora crassa and Aquifex aeolius is homologous to nucleotide-sugar epimerases and hydroxysteroid dehydrogenases while seeking distant homologs of these enzymes with a hidden Markov model-based search of Genpept. This homology allows us to use information from the solved three-dimensional structures of nucleotide-sugar epimerases and hydroxysteroid dehydrogenases and our motif analysis of these enzymes to predict functional domains on their homologs in complex I. Received 26 November 1998; received after revision 12 January 1999; accepted 12 January 1999     

A method for the fluorimetric determination of 4-(2-Hydroxy-3-isopropylaminopropoxy)-indole (LB 46), aβ-blocking agent,in plasma and urine

Zusammenfassung Eine empfindliche fluorimetrische Methode zur Bestimmung von 4-(2-Hydroxy-3-isopropylaminopropoxy)-indol, dem-Blocker LB 46, in Plasma (Erfassungsgrenze 0,02 g) und in Urin (Erfassungsgrenze 0,05 g) wird beschrieben. Die mit dieser Methode gemessene biologische Halbwertszeit im Plasma beträgt nach peroraler Verabreichung beim Menschen 3 h und bei der Ratte etwa 30 min.     

Cyclin A1 is a p53-induced gene that mediates apoptosis, G2/ M arrest, and mitotic catastrophe in renal, ovarian, and lung carcinoma cells

We were the first to identify cyclin A1 as a p53-induced gene by cDNA expression profiling of p53-sensitive and -resistant tumor cells [Maxwell S. A. and Davis G. E. (2000) Proc. Natl. Acad. Sci. USA 97, 13009–13014]. We show here that cyclin A1 can induce G2 cell cycle arrest, polyploidy, apoptosis, and mitotic catastrophe in H1299 non-small cell lung, TOV-21G ovarian, or 786-0 renal carcinoma cells. More cdk1 protein and kinase activities were observed in cyclin A1-induced cells than in GFP control-induced cells. Thus, cyclin A1 might mediate apoptosis and mitotic catastrophe through an unscheduled or inappropriate activation of cdk1. Two primary renal cell carcinomas expressing mutated p53 exhibited reduced or absent expression of cyclin A1 relative to the corresponding normal tissue. Moreover, renal carcinoma-derived mutant p53s were deficient in inducing cyclin A1 expression in p53-null cells. Cyclin A1 but not cyclin A2 was upregulated in etoposide-treated tumor cells undergoing p53-dependent apoptosis and mitotic catastrophe. Forced upregulation of cyclin A2 did not induce apoptosis. The data implicate cyclin A1 as a downstream player in p53-dependent apoptosis and G2 arrest. Received 1 November 2005; received after revision 17 February 2006; accepted 13 April 2006