Quantitative structure-activity analyses of nitrobenzene toxicity to Tetrahymena pyriformis

Toxicity data for the 50% growth inhibitory concentration against Tetrahymena pyriformis (log (IGC50-1)) for 42 alkyl- and halogen-substituted nitro- and dinitrobenzenes were obtained experimentally. Log (IGC50-1) along with the hydrophobicity, the logarithm of the 1-octanol/water partition coefficient (log Kow), and the molecular orbital properties, the lowest unoccupied molecular orbital energy (Elumo) and maximum acceptor superdelocalizability (Amax), were used to develop quantitative structure-activity relationships (QSARs). All the nitroaromatic compounds tested had toxicity in excess of baseline, nonpolar narcosis. The nitrobenzenes were thought to elicit their toxic response through multiple (and mixed) mechanisms. No high-quality relationship was observed between toxicity and hydrophobicity, or Elumo, individually. However, a strong relationship ?log (IGC50-1) = 16.4(Amax) - 4.64; n = 42, r2 = 0.847, s = 0.279, F = 229? was obtained. In an effort to improve predictability, two-parameter QSAR, or response surface, analyses were performed. These analyses resulted in the following QSARs: ?log (IGC50-1) = 0.206(log Kow) - 16.0(Amax) - 5.04; n = 42, r2 = 0.897, s = 0.229, F = 180? and ?log (IGC50-1) = 0.467(log Kow) - 1.60(Elumo) - 2.55; n = 42, r2 = 0.881, s = 0.246, F = 154?.     

Structure-toxicity relationships for aminoalkanols: a comparison with alkanols and alkanamines

The relative toxicity (log IGC50(-1)) of 49 selected aliphatic amines and aminoalkanols was evaluated in the static Tetrahymena pyriformis population growth impairment assay. Excess toxicity, indicated by potency greater than predicted for non-polar narcotic alkanols, was associated with both classes of test chemicals. Moreover, the aminoalkanols were found to be more toxic than the corresponding alkanamines. A high quality 1-octanol/water partition coefficient (log K(ow)) dependent quantitative structure-activity relationship (QSAR), logIGC50(-1) = 0.78 (log K(ow)) - 1.42; r2 = 0.934, was developed for alkanamines. This QSAR represented the amine narcosis mechanism of toxic action. No quality QSAR was developed for the aminoalkanols. However, several structure-toxicity features were observed for this class of chemicals. Two-amino-1-hydroxy derivatives being more toxic than the corresponding derivatives, where the amino and hydroxy moieties were separated by methylene groups. Hydrocarbon branching next to the amino moiety resulted in decreased toxicity. Aminoalkanol alters lipid metabolism in T. pyriformis.     

Quantitative structure-based modeling applied to characterization and prediction of chemical toxicity

Quantitative modeling methods, relating aspects of chemical structure to biological activity, have long been applied to the prediction and characterization of chemical toxicity. The early linear free-energy approaches of Hansch and Free Wilson provided a fundamental scientific framework for the quantitative correlation of chemical structure with biological activity and spurred many developments in the field of quantitative structure-activity relationships (QSARs). In addition to modeling of chemical toxicity, these methods have been extensively applied to modeling of medicinal properties of chemicals. However, there are important differences in the nature and objectives of these two applications, which have led to the evolution of different modeling approaches (namely, the need for treating sets of noncongeneric toxic compounds). In this paper are discussed those approaches to chemical toxicity that have taken a more "personalized" configuration and have undergone implementation into software programs able to perform the various steps of the assessment of the hazard posed by the chemicals. These models focus both on a variety of toxicological endpoints and on key elements of toxicity mechanisms, such as metabolism.     

History of chloroform anesthesia

The first narcosis with chloroform was performed by James Young Simpson on himself on November 4, 1847. The chemical substance had been first produced in 1831 almost simultaneously in the USA by Samuel Guthrie and in France by Eugène Soubeiran. Knowledge of the narcotic effect of chloroform spread rapidly, but very soon reports of sudden deaths mounted. The first fatality was a 15-year-old girl called Hannah Greener, who died on January 28, 1848. The opponents and supporters of chloroform were mainly at odds with the question of whether the complications were solely due to respiratory disturbance or whether chloroform had a specific effect on the heart. Between 1864 and 1910 numerous commissions in UK studied chloroform, but failed to come to any clear conclusions. It was only in 1911 that Levy proved in experiments with animals that chloroform can cause cardiac fibrillation. The reservations about chloroform could not halt its soaring popularity. Between about 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in UK and German-speaking countries. In America, however, there was less enthusiasm for chloroform narcosis. In Germany the first comprehensive surveys of the fatality rate during anaesthesia were made by Gurlt between 1890 and 1897. In 1934, Killian gathered all the statistics compiled until then and found that the chances of suffering fatal complications under ether were between 1: 14,000 and 1: 28,000, whereas under chloroform the chances were between 1: 3,000 and 1: 6,000. The rise of gas anaesthesia using nitrous oxide, improved equipment for administering anaesthetics and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis. In 1947, Ralph Waters attempted to reactivate chloroform, but failed. Possibly as a result of these efforts, however, chloroform played a role in American publications longer than elsewhere. The story of the clinical use of chloroform ended in 1976 with the second edition of V. J. Collins' textbook.     

In situ analysis of adhesion molecule expression in kidneys infected with murine malaria

Two toluene-sensitive mutants were generated from Pseudomonas putida IH-2000, the first known toluene-tolerant isolate, by Tn5 transposon mutagenesis. These mutants were unable to grow in the presence of toluene (log P(ow) 2.8) but they could grow in medium overlaid with organic solvents having a log P(ow) value higher than that of toluene such as p-xylene (log P(ow) 3.1), cyclohexane (log P(ow) 3.4) and n-hexane (log P(ow) 3.9). The Tn5 transposable element knocked out a cyoB-like gene in one mutant and a cyoC-like gene in the other mutant. Seven open reading frames were found in a 5.5-kb region containing the cyoB- and cyoC-like genes of strain IH-2000. ORFs 3.7 showed significant identity to the cyoABCDE gene products of Escherichia coli, but ORFs 1 and 2 showed no significant homology to any protein reported so far. The growth patterns of the Tn5 mutants with the inactivated cyo-like gene were similar to that of the wild-type strain in the absence of organic solvents, although the doubling times were slightly longer than that of the wild-type strain. Our findings indicate that cyo is an important gene for toluene tolerance, although its role is still unclear.     

Covalent modifications of aminophospholipids by 4-hydroxynonenal

Lipid oxidation is implicated in a wide range of pathophysiological disorders, which leads to reactive compounds such as aldehydes. Among them 4-hydroxynonenal (4-HNE) reacts strongly with the NH2 groups of amino acids and forms mainly Michael adducts and minor Schiff-base adducts. Such reactions occur also with compounds containing thiol groups. No data are available describing 4-HNE interactions with amino-phospholipids. To investigate such a possibility, 4-HNE was incubated with either phosphatidylethanolamine (PE) or phosphatidylserine (PS) in an aqueous-organic biphasic system and the resulting products were identified by liquid chromatography-mass spectrometry (LC-MS). Our study points out the potential capacity of 4-HNE to react with phospholipids containing amino groups and particularly PE. The main resulting compounds found were a Michael adduct plus a minor Schiff base adduct, which was partly cyclized as a pyrrole derivative via a loss of water. Its stabilization as a pyrrole derivative allows to differentiate 4-HNE from the other aldehydes generated via lipid oxidation (e.g., malondialdehyde, 2-nonenal) that lack the 4-hydroxyl group. Their formation seems not to be affected when the pH varies from 6.5 to 8.5. Surprisingly, PS reacted poorly producing only a small amount of Michael adduct, the Schiff-base adduct being nondetectable. We conclude that such adducts, if they are formed in cell membranes, could alter the phospholipase-dependent cell signaling.     

Deterioration of goat spermatozoa in skimmed milk-based extenders as a result of oleic acid released by the bulbourethral lipase BUSgp60

The migration behavior and separation of six tetracyclines (TCs) were investigated by micellar electrokinetic chromatography (MEKC) in the pH range 5.0-9.0 using ammonium acetate buffer with the addition of sodium dodecyl sulfate (SDS). Mixed SDS-Brij 35, sodium cholate (SC) and tetradecyltrimethylammonium bromide (TTAB) were also used as surfactants. The influences of surfactant concentration and buffer pH on the separation of TCs were examined and the separations of TCs were optimized. Complete separation of six TCs was achieved within 8 min with 15 mM ammonium acetate buffer containing 20 mM SDS, with or without the addition of Brij 35 (0.135%, w/v), at pH 6.5 using a fused-silica capillary (42 cm x 75 microns I.D.) at 15 kV. In general, good linear correlations of the logarithm of migration factor (log k') versus the logarithm of octanol-water partition coefficient (log P(ow)) in these micellar systems, except for the TTAB-MEKC system, were obtained. The results indicate that the migration of TCs in MEKC is mainly based on hydrophobic interactions. However, hydrogen bonding interactions also play a significant role in influencing the chemical selectivity of TCs. In addition, the micelle-water partition coefficients (Pmw) of TCs, which are pH-dependent in the SDS-MEKC micellar system, are reported.     

Involvement of glutamate 399 and lysine 192 in the mechanism of human liver mitochondrial aldehyde dehydrogenase

Mutation to the conserved Glu399 or Lys192 caused the rate-limiting step of human liver mitochondrial aldehyde dehydrogenase (ALDH2) to change from deacylation to hydride transfer (Sheikh, S., Ni, L., Hurley, T. D., and Weiner, H. (1997) J. Biol. Chem. 272, 18817-18822). Here we further investigated the role of these two NAD+-ribose-binding residues. The E399Q/K/H/D and K192Q mutants had lower dehydrogenase activity when compared with the native enzyme. No pre-steady state burst of NADH formation was found with the E399Q/K and K192Q enzymes when propionaldehyde was used as the substrate; furthermore, each mutant oxidized chloroacetaldehyde slower than propionaldehyde, and a primary isotope effect was observed for each mutant when [2H]acetaldehyde was used as a substrate. However, no isotope effect was observed for each mutant when alpha-[2H]benzaldehyde was the substrate. A pre-steady state burst of NADH formation was observed for the E399Q/K and K192Q mutants with benzaldehyde, and p-nitrobenzaldehyde was oxidized faster than benzaldehyde. Hence, when aromatic aldehydes were used as substrates, the rate-limiting step remained deacylation for all these mutants. The rate-limiting step remained deacylation for the E399H/D mutants when either aliphatic or aromatic aldehydes were used as substrates. The K192Q mutant displayed a change in substrate specificity, with aromatic aldehydes becoming better substrates than aliphatic aldehydes.     

Ti(C,N)基金属陶瓷功能梯度材料的制备

介绍了Ti(C,N)基金属陶瓷功能梯度材料的主要制备技术，即真空烧结后氮化处理和直接在N2气氛中烧结；对两种技术所制得的金属陶瓷的成分分布，表层及过渡层的组织和性能特点进行了总结；并结合热力学计算结果，论述了其显微组织的形成机理；最后对今后的研究方向提出了建议。     

Effects of potassium depletion on control of breathing in awake rats

Possible mechanisms for the variable ventilatory response to metabolic acid-base disturbances have been examined in normal and K-depleted rats. Ventilatory measurements are correlated with CSF acid-base data. The ratios VE/VO2 and 1/PaCO2 are utilized as indices of alveolar ventilation. The log of these indices correlates closely with CSF [H+] independent of [K+] except at very low CSF [H+] where the change in log 1/PaCO2 and log VE/VO2 per change in CSF [H+] is much diminished in low-K rats. This finding suggests the presence of an additional stimulus to breathing in the low-K rat opposing the inhibitory effect of low CSF [H+]. Otherwise the chemical control of ventilation appears to be normal. However, low-K rats always breath with a low-flight-Vt pattern and occasionally with abnormal rhythms. The similarity of the low K breathing pattern to that reported in awake animals with vagotomy and pneumotaxic center (PC) lesions suggests that the altered breathing pattern in depletion involves vagal and/or PC pathways. The similarity of the low-K breathing pattern to that observed with reserpine administration together with the known relationships of K and catecholamine metabolism lead to the speculation that K depletion alters breathing via an effect on central catecholamine metabolism. However, other mechanisms involving changes in membrane excitability and intracellular pH in K depletion might also be involved.