Study of man during a 56-day exposure to an oxygen-helium atmosphere at 258 mm. Hg total pressure. II. Major and minor atmospheric components.
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Adult↗
Biomedical subjects
J D Adams
Publications and source records attributed to J D Adams.
Hepatic glutathione homeostasis in the rat: efflux accounts for glutathione turnover.
Hepatic glutathione turnover and the efflux of glutathione from the liver into bile and blood were measured in male Sprague-Dawley rats in vivo. In fed rats the efflux of glutathione into blood, calculated from the hepatic arteriovenous concentration gradient and hepatic blood flow, amounted to 12.4 +/- 1.4 nmoles min X gm liver. Together with the excretion of glutathione into bile (3.4 +/- 0.4 nmoles per min X gm liver) total efflux accounted for the hepatic turnover of glutathione of 15.2 +/- 0.9 nmoles per min X gm liver. Fasting animals for 48 hr markedly increased hepatic glutathione turnover to 26.4 +/- 1.2 nmoles per min X gm liver. Increased efflux into blood rather than increased intrahepatic catabolism accounted for this increased turnover. The systemic clearance of glutathione was 3.22 +/- 0.51 ml per min X 100 gm body weight. The efflux of glutathione from liver therefore was calculated to contribute over 90% of total glutathione inflow into the circulation, as determined from the clearance and the arterial concentration of glutathione. Thus, the liver is the major source of plasma glutathione, and turnover of hepatic glutathione in the basal state is accounted for almost entirely by efflux of glutathione from the liver. During fasting, the plasma clearance of exogenous glutathione increased to 5.32 +/- 0.35 ml per min X 100 gm body weight, and the utilization of methionine for glutathione synthesis increased markedly. The increased extrahepatic catabolism during fasting results in a decrease in plasma glutathione, which in turn may account for the observed increase in sinusoidal glutathione efflux with concomitant stimulation of the rate of hepatic glutathione turnover and of synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The effects of aging and neurodegeneration on apoptosis-associated DNA fragmentation and the benefits of nicotinamide.
In this work, the tertiary butylhydroperoxide- (t-BuOOH) treated mouse was used as a model to study the oxidative stress that is associated with various neurodegenerative diseases. DNA was found to be an early target of t-BuOOH attack. Necrosis was associated with extensive DNA fragmentation that occurred in almost all regions of the brain within 20 min following intracerebroventricular (icv) injection of 109.7 mg/kg t-BuOOH. Apoptosis was associated with high levels of DNA fragmentation that was observed at 48 h after icv administration of 21.9 mg/kg t-BuOOH. Susceptibility to DNA damage was found to be age-dependent, since 24-mo-old mice exhibited consistently higher and more pervasive DNA damage than 8 mo-old-mice. Extensive DNA damage was seen in various brain regions in patients with Alzheimer disease (AD) and with both Alzheimer and Parkinson disease (AD-PD). These results directly implicate DNA damage in neurodegeneration. The DNA fragmentation ob-served can lead to both apoptosis and necrosis, as suggested by gel electrophoresis. Nicotinamide, a precursor of NAD in the brain, was able to prevent DNA fragmentation induced by low-dose t-BuOOH, when coadministered with the toxin.
Aged↗
The acute histopathology of MPTP in the mouse CNS.
We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rapidly induced cytopathological changes in the brain, involving some neurons selectively, as well as astrocytes and blood vessels. Dopaminergic neurons in the midbrain, as identified by immunostaining for tyrosine hydroxylase, were damaged as early as 2.5 hr after MPTP administration. Ultrastructurally, there was disruption of the endoplasmic reticulum and cytoplasmic condensation and vacuolation of the tyrosine hydroxylase reactive neurons in the substantia nigra as well as their axon terminals in the striatum. Perivascular edema was associated with vacuolation and swelling of astrocytic cytoplasm and rupture of perivascular foot processes. There was also capillary and arteriolar endothelial damage. Surprisingly, there was no clear correlation of MPTP-induced pathology with mitochondrial damage in any cell type. Biochemically, dopamine was depleted in the substantia nigra and the striatum within a few hours following MPTP administration. However, in the substantia nigra, homovanillic acid (HVA), one of the metabolites of dopamine, showed relatively less depletion than did dopamine by MPTP. These results may indicate that the turnover of dopamine was stimulated in the brain as a homeostatic mechanism.
Animals↗
Isolation and identification of 3-hydroxy-3-methyloxindole, the major murine metabolite of 3-methylindole.
3-Methylindole (3MI) is pneumotoxic to ruminants and rodents subsequent to metabolic oxidative activation by cytochrome P-450 monooxygenases. Goats are much more susceptible than mice and rats to 3MI-mediated lung damage, and these differences in species susceptibility may be reflected by differences in the metabolic products of 3MI. Radioactive 3MI was administered ip to Swiss-Webster mice, and the major nonpolar urinary metabolites were fractionated and separated by HPLC. Although 3-methyloxindole has been shown to be the major urinary metabolite of 3MI in goats, it was not detected in mouse urine. Instead, the major metabolite, 3-hydroxy-3-methyloxindole, was isolated and purified and its structure elucidated by 1H and 13C NMR, mass spectrometry, and IR spectroscopy. This is the first identification of this highly oxidized indole from mammalian sources. The production of this metabolite may be indicative of the formation of an electrophilic methyleneoxindole intermediate, which could be responsible for pneumotoxicity in this species.
Animals↗
Tyrosine hydroxylase: mechanisms of oxygen radical formation.
A new mechanism of oxygen radical formation in dopaminergic neurons is proposed, based on the oxidative mechanism of tyrosine hydroxylase. The cofactor (6R,6S)-5,6,7,8-tetrahydrobiopterin can rearrange in solution which allows an autoxidation reaction producing O2.-, H2O2 and HO.. The combination of tyrosine hydroxylase and the cofactor produces more oxygen radicals than does the autoxidation of the cofactor. This production of oxygen radicals could be damaging to dopaminergic neurons. In the presence of tyrosine, the enzyme produces less radicals than it does in the absence of tyrosine. Mechanisms are proposed for the generation of reactive oxygen species during the autoxidation of the cofactor and during enzymatic catalysis. The generation, by tyrosine hydroxylase, of very small amounts of oxygen radicals over the period of 65 years could contribute to the oxidative stress that causes Parkinson's disease.
Animals↗
Selenium in particulates and gaseous fractions of smoke from cigarettes prepared from tobacco grown on fly-ash-amended soil.
Cigarettes prepared from tobacco grown in pots of soils amended with soft coal fly ash were smoked, and the mainstream and gaseous fractions were analyzed for total selenium concentration. Fly-ash-grown and control (soil-grown) tobaccos contained, respectively, 0.79 and 0.03 ppm selenium. The quantities of selenium (ng per cigarette) found in the mainstream particulate and gaseous fractions were, respectively, 62.4 and 246.0 for the fly-ash-grown and 8.6 and 12.0 for the control treatments. Studies of the absorption, retention, effects, metabolism, and excretion of selenium in the body are reviewed.
Carbon↗
Chemical studies on tobacco-specific N-nitrosamines in the smoke of selected cigarettes from the U.S.A., West Germany, and France.
Studies on the variations of biologically important smoke constituents of popular cigarettes in several European countries and in the United States include investigations on the types and levels of volatile (VNA) and tobacco-specific nitrosamines (TSNA). GLC-TEA and HPLC-TEA methods are used to determine the VNA and TSNA in mainstream and sidestream smoke of cigarettes. This report presents data on the smoke of some West German cigarettes which demonstrate that the VNA levels are about the same as those in the smoke of U.S. cigarettes; but that they are lower than those in the smoke of French cigarettes, made of dark tobacco types. The tobacco-specific nonvolatile N-nitrosamines determined in the mainstream smoke of commercial U.S. blended cigarettes (N-nitrosoanatabine, N-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone together) ranged from 680 to 830 ng per cigarette, while those for commercial West German products ranged from 340 to 780 ng per cigarette in nonfilter brands and from 180 to 450 ng in filter-tipped cigarettes. The analyzed French products contained 1010 to 1380 ng of these compounds in the smoke of each cigarette.
Chromatography, Gas↗
Quinoline and methylquinolines in cigarette smoke: comparative data and the effect of filtration.
A method has been developed to determine quantitatively quinoline, isoquinoline, and each of the methylquinoline isomers in cigarette smoke. This method was applied to the smoke of several different commercial cigarettes with and without filter tips. Quantitative analyses were accomplished by capillary gas chromatography, using a 50-m OV-101 fused silica capillary column and a 50-m Dexsil 300 fused silica column. Quinoline, isoquinoline and all seven of the methylquinolines were found in cigarette smoke. When cigarettes were analyzed with and without filter tips, these compounds were reduced by filtration, but not as much as tar was reduced. The significance of these data is discussed in view of the biological activity of specific isomers of these environmental pollutants.
Chromatography, Gas↗
Inhibition of 3-methylindole bioactivation by the cytochrome P-450 suicide substrates 1-aminobenzotriazole and alpha-methylbenzylaminobenzotriazole.
The cytochrome P-450 suicide substrates 1-aminobenzotriazole (ABT) and alpha-methylbenzylaminobenzotriazole (alpha MB) were used as probes to examine the participation of cytochrome P-450 monooxygenases in the metabolism and covalent binding of 3-methylindole. ABT was a potent inactivator of 3-methylindole turnover and covalent binding of [methyl-14C]3-methylindole to protein in goat lung microsomal incubations. Both covalent binding and 3-methylindole turnover were decreased approximately 50% at 0.01 mM and 100% at 0.1 mM concentrations of ABT. The effects of ABT indicated that toxicity, as related to covalent binding, was directly dependent upon cytochrome P-450 catalysis. The inactivation of 3-methylindole turnover was greater with a 0.01 mM concentration of the isozyme-selective inhibitor alpha MB, 74% as compared with 47% for ABT. alpha MB (0.01 mM) decreased benzphetamine N-demethylase activity by 82% but decreased 7-ethoxyresorufin O-deethylase activity by only 28%. Thus, both 3-methylindole metabolism and benzphetamine oxidation were selectively inactivated by alpha MB. These findings suggest that 3-methylindole is metabolized to alkylating, electrophilic intermediates preferentially by the homologues of "phenobarbital-inducible" isozymes (presumably forms 2 and 5 in analogy to rabbit lung isozymes) to cytochrome P-450 in pulmonary microsomes, rather than by the polycyclic aromatic hydrocarbon-inducible isozymes.
Animals↗
Metabolism of phencyclidine. The role of iminium ion formation in covalent binding to rabbit microsomal protein.
Incubation of phencyclidine (PCP) with rabbit liver microsomes and Na14CN resulted in the metabolically dependent formation of a 14C-labeled cyano adduct of the drug. After isolation by HPLC, this compound was identified as the alpha-aminonitrile [1-(1-phenylcyclohexyl)-2-cyanopiperidine] derivative of PCP by use of chemical-ionization and gas-chromatographic coupled electron-impact mass spectrometry. Synthetic alpha-aminonitrile exhibited identical chemical properties and comigrated in HPLC and GLC with the metabolism derived cyano adduct. Molecular identification of the adduct formed by cyanide trapping provided evidence for the formation of an iminium ion during PCP metabolism. Quantitative estimation by HPLC demonstrated that the alpha-aminonitrile accounted for over 50% of the PCP metabolized in 30 min by hepatic microsomes in vitro. Metabolism-dependent covalent binding of [3H]PCP to rabbit liver microsomal proteins was inhibited by cyanide ion in a concentration-dependent manner with an IC50 value of 57 microM. The concentrations of cyanide ion used in these experiments did not significantly inhibit the metabolism of PCP. These results support our suggestions that iminium ion formation may represent an important intermediary step in the metabolism of PCP and that such a reactive electrophilic species may be capable of covalent interactions with nucleophilic groupings on microsomal macromolecules.
Animals↗
A survey of the accuracy of references in 10 dental journals.
Several studies have evaluated the accuracy of bibliographic citations in the medical literature. The purpose of this study was to evaluate the accuracy of 300 reference citations in 10 dental journals. Thirty references were randomly selected from the January 1991 issue of 10 dental journals, for a total of 300 reference citations. Almost all of the citations were verified from the original source; a few were identified from other library sources. Only two references were unable to be identified, and they were both from foreign journals. This survey found 78% (n = 234) of the citations verified (n = 298) to be correct.
Abstracting and Indexing↗