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Biomedical subjects

D W Nebert

Publications and source records attributed to D W Nebert.

At least 343 records · Page 19Linked to original sources
PubMed1966

Environmental factors influencing the hyperfine structure of manganous low-temperature electron paramagnetic resonance spectra.

Hyperfine structure is observed in low temperature (T = -180 degrees C) EPR (electron paramagnetic resonance) spectra of a number of solutions containing Mn(++) ions 13, 15) which have characteristics in common with low temperature EPR spectra from biological substances such as mitochondria and microsomes (1-4). This investigation is an attempt to understand the features of these signals in terms of the molecular environment of the manganous ion, and a qualitative explanation for the observations reported here is advanced in terms of the amount of axial distortion of a manganese hydrate in different environments.

Chlorides↗
PubMedDate not supplied

CYP2D1 polymorphism in methamphetamine-treated rats: genetic differences in neonatal mortality and effects on spatial learning and acoustic startle.

d-Methamphetamine (MA) is one of more than two dozen drugs included in the cytochrome P450-mediated "debrisoquine oxidation polymorphism" panel. The human gene (CYP2D6) is responsible for the "poor metabolizer" (PM) and "extensive metabolizer" (EM) phenotypes for drugs such as MA; a similar polymorphism (the CYP2D1 gene) exists in rats. Female Black or Dark Agouti rats exhibit the PM phenotype, whereas Sprague-Dawley (SD) rats show the EM trait. We sought to test the possibility that these strains of rats might exhibit altered MA-induced developmental neurotoxicity. Neonatal exposure to MA on days 11-20 has previously been shown to induce spatial learning deficits in Sprague-Dawley rats when tested as adults. Therefore, in the present experiment, on postpartum days 11 through 20, ACI (Black Agouti) and SD progeny were administered 30 mg/kg MA twice daily. MA treatment caused larger increases in mortality in ACI than in SD rats, suggesting that decreased MA metabolism leads to enhanced toxicity and lethality. Female offspring were assessed behaviorally as adults. No differences were observed in acoustic startle or straight swimming channel performance. In the Morris maze, both MA-treated rat strains showed longer latencies to find the hidden platform during acquisition, reinstatement, and shift trials, and spent less time in the target quadrant on probe trials; no strain differences in learning were found. Although these data do not support our hypothesis that MA-induced developmental neurotoxicity might be enhanced in the ACI rat, this interpretation is tempered by the high mortality rate (65%) of MA-treated ACI neonates, suggesting a possible "survivor effect" in this strain.

Acoustic Stimulation↗
PubMedDate not supplied

Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells.

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoacyltransferases↗
PubMedDate not supplied

Trout P450IA1: cDNA and deduced protein sequence, expression in liver, and evolutionary significance.

The cytochrome P1(450) (P450IA1) cDNA has been isolated and sequenced from liver of 3-methylcholanthrene-treated rainbow trout (Salmo gairdneri). The cDNA hybridizes to a 2.8-kb mRNA that is induced at least 10-fold by 3-methylcholanthrene. Southern blot analysis suggests the presence of a single gene or a very small number of genes. An open reading frame of the 2573-bp cDNA encodes a 522-residue protein (Mr = 59,241) that is more similar to the mammalian P450IA1 than the mammalian P450IA2 proteins. The aromatic hydrocarbon (Ah) receptor, responsible for mammalian P450IA1 and IA2 inducibility, was detected in trout liver cytosol by specific binding to [1,6-3H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vitro. Comparison of the fish P450IA1 protein with human, mouse, rat and rabbit P450IA1 and P450IA2 proteins reveals the presence of a remarkably large number of single amino acids and stretches of 2-6 residues in a row that are invariant among these nine P450 proteins. These conserved regions may participate in the binding of the NADPH-P450 oxidoreductase flavoprotein, substrate, or heme.

Amino Acid Sequence↗