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Propane sultone (PS) injected i.p. 24 or more hours before Friend leukemia virus increased the incidence of lymphoma in SJL/J mice and at a higher dose increased the incidence of erythroleukemia in B10SJF1 mice. PS at the same time also decreased hematopoietic stem cell clonogenicity.
The potential usefulness of a zwitterionic detergent, 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHPAS), in the stabilization of acidic and basic fibroblast growth factors (FGFs) was examined. Among several detergents, CHAPS was found to be not only non-cytotoxic but also most useful in handling the diluted preparations of FGFs. The advantages are as follows: 1) at lower concentrations than 0.01% CHAPS did not affect growth factor activity of calf serum (CS) and the growth rate of BALB/c 3T3 cells. The primary culture of rat prostate epithelium and colony formation of NRK-49F cells were hardly influenced by CHAPS lower than 0.003%; 2) the loss of FGFs that usually occurs due to their adherence to the surface of storage containers was effectively prevented by inclusion of 0.1% CHAPS; 3) the recovery of FGFs after storage or dialysis was significantly enhanced by inclusion of 0.1% CHAPS; 4) CHAPS at lower concentrations than 0.1% does not interfere with amino acid analysis, except that Thr may be misled only when the ratio of protein/CHAPS is low; 5) amino acid sequence analysis was hardly disturbed by CHAPS up to 0.5%. These results indicate that CHAPS is useful as a stabilizing agent for various kinds of polypeptides capable of showing biological activity at a low concentration.
Novel mutual pro-drugs in which 2',3'-dideoxyinosine anti-HIV (human immunodeficiency virus) drug and 3-octadecyloxy-propane-1,2-diol anti-inflammatory drug were attached to the same molecule via different biodegradable linkages, were synthesized through two-step enzymatic transesterification by a commercial lipase in acetone.
Mucor miehei protease (EC 3.4.21 -- ), an acid protease of fungal origin, was rapidly inhibited at pH 5.0 and 10 degrees C by a 78-fold molar excess of diazoacetyl norleucine methyl ester (N2Ac-Nle-OMe) when simultaneously added with a 78-fold molar excess of Cu(II). Preincubation with Cu(II) before the addition of N2Ac-Nle-OMe reduced the initial rate of activity loss presumably due to a copper-induced structural change as deduced from an examination of CD spectra. Cof norleucine and 1.02 +/- 0.041 mol of copper. The conformation of the N2Ac-Nle-OMe-inhibited enzyme appeared to be somewhat altered since the rate of H-3H exchange determined for the slowest exchanging class of hydrogens was reduced by more than 10-fold although the estimated number of hydrogens in this class remained constant. Mucor miehei protease was also inhibited by pepstatin; complete inactivation required a 6-fold molar excess of inhibitor and was associated with a major conformational change as determined from CD spectra. Loss of activity also occurred in the presence of 1,2-epoxy-3-(p-nitrophenyoxy)propane (EPNP).
Intramolecular excimer formation of 1,3-di(2-pyrenyl)propane was used to study the fluidity of liposomes prepared from membrane polar lipids of Bacillus stearothermophilus. On the basis of spectral data, local polarity and polarizability parameters were established suggesting that the probe molecules are located well inside the membranes, but displaced towards the polar head groups of the phospholipid molecules. The excimerization rate is very sensitive to lipid phase transitions and pretransitions of synthetic pure lipid bilayers. In bacterial lipids from cultures grown at 55 and 68 degrees C, thermal profiles of excimer to monomer intensity ratios (I'/I) show a broad transition which is displaced to higher temperatures in response to the increase of the growth temperature; these results correlate well with differential scanning calorimetry data and fluorescence polarization of diphenylhexatriene. Additionally, lipid bilayers of bacteria grown at 68 degrees C exhibit a decreased membrane fluidity, as monitored by both fluorescent probes.
To determine correlations between the biological action pattern and chemical reactivity of alkylating agents, the rate constants for reactions of 1,3-propane sultone and 1,4-butane sultone with a series of nucleophiles at 37 degrees C have been determined. Previously published data on the mutagenicity of the two sultones and of some alkyl methanesulfonates and dialkyl sulfates towards Schizosaccharomyces pombe have been used in the evaluation of the dependence of mutagenic effectiveness on chemical reactivity. It is of interest to note that the mutagenic effectiveness of the two sultones, if expressed per alkylating event at a certain low nucleophilicity is the same as that of e.g. methyl methanesulfonate and ethyl methanesulfonate.
Propane-1,2-diol (propylene glycol, PG) permeates more rapidly than glycerol, has a strong glass-forming tendency, and appears to have a low toxicity. It is therefore attractive as a potential cryoprotectant for renal preservation. In this paper we compared the effect on subsequent function, of exposing rabbit renal cortical slices to 1 M PG or glycerol in a range of vehicle solutions and we demonstrated a remarkably low toxicity of PG at this concentration. Rabbit kidneys were then perfused with solutions containing PG up to a maximum concentration of 3 M, after which the cryoprotectant was removed and the function of cortical slices prepared from the perfused kidneys was assessed. Marked differences in perfusion characteristics were found between PG and glycerol and between different vehicle solutions for PG, but the two most suitable perfusates, both containing about 100 mM mannitol, permitted normal function in slices prepared after removal of PG. These results indicate that, with an appropriate vehicle perfusate, exposure to PG up to a concentration of 3 mol/liter has remarkably little effect upon vascular resistance and the renal cortical functions measured.
The permeability of human platelets to glycerol (GLY) and propane-1,2-diol (propylene glycol, PG) has been determined by measuring the time course of their change in volume following abrupt immersion in solutions of these solutes. A simple light-scattering method, and its calibration to measure mean platelet volume is described. The data are analyzed by means of the Kedem-Katchalsky (K-K) equations, modified to take into account the nonideal behavior of both intracellular and extracellular solutes. The values of the K-K parameters at 2, 21, and 37 degrees C, respectively, were as follows: the hydraulic conductivities (Lp) were 1 x 10(-7), 7 x 10(-7) and 3 x 10(-6) cm.sec-1.atm-1; the solute permeabilities for PG (omega RTPG) were 1.9 x 10(-6), 2.8 x 10(-5), and 1.3 x 10(-4) cm.sec-1; the solute permeabilities for GLY (omega RTGLY), at 21 and 37 degrees C only, were 2.6 x 10(-7) and 1.4 x 10(-6) cm.sec-1. The reflection coefficient (sigma) was 1 throughout. The relevant activation energies were -Lp, 16.5 kcal.mol-1; omega RTPG, 20.5 kcal.mol-1; and omega RTGLY, 17.9 kcal.mol-1. The use of these data is illustrated by computing schedules for the addition and removal of GLY and PG so that the amplitudes of changes in platelet volume are held within predetermined limits.
The preceding papers in this series have described techniques that permit the introduction and removal of propane-1,2-diol (propylene glycol, PG) with human platelets, in concentrations up to 2 M, without producing serious damage. These methods have now been used in attempts to cryopreserve platelets, with assessment of survival by the hypotonic stress response and ADP-induced aggregation. PG concentrations of 0.5, 1.0, 2.0, and 2.5 M and cooling rates between 0.4 and 100 degrees C/min were studied. The maximum response in the hypotonic stress test was no better than 17% and the greatest ADP-induced aggregation was only 6%; these results were obtained with 0.5 M PG, a cooling rate of 14 degrees C/min, and rapid warming (approximately 150 degrees C/min). The failure of PG concentrations greater than 0.5 M to improve survival was unexpected. When cooling was interrupted at progressively lower temperatures and function assessed, it was possible to relate the extent of damage to temperature and then, with the aid of phase diagrams, it was possible to show that, irrespective of the initial concentration of PG, the extent of damage was closely correlated with the concentration of PG produced at the minimum temperature used. It is concluded that the toxicity of PG increases so steeply with the increasing concentration produced by the separation of ice during freezing that this effect is sufficient to counteract the cryoprotective action of this solute for platelets.
Pre- and post-treatments with caffeine enhanced propane sultone (PS)-induced growth damage in barley. The caffeine post-treatments were, however, more effective in potentiating PS-induced growth damage and caused an additive effect on the frequency of chlorophyll mutations.
The glucosinolate hydrolysis product 1-isothiocyanato-3-(methylsulfinyl)-propane (IMSP), also known as iberin, is consumed in the average human (US) diet at approximately 1 mumol/kg/day. The chemoprotective effects observed with the consumption of cruciferous vegetables may be due to the presence of specific glucosinolate hydrolysis products either within the crucifers, or formed after ingestion of the crucifers. The mechanism of chemoprotection may be through selective induction of components of Phase II xenobiotic metabolizing enzymes. The influence of repeated administration of low concentrations of IMSP by gavage on components of Phase I and Phase II xenobiotic metabolizing systems was examined in the liver and small intestine of male Fischer 344 rats. Doses of 1, 10 and 100 mumol IMSP/kg, administered by gavage for 7 days, did not alter weight gain, or hepatic and renal weights, relative to body weight, and did not cause any histological lesions. Intestinal glutathione S-transferase (GST) activity and NAD(P)H:quinone reductase (QR) activities were significantly elevated to 3.1 and 8.1 times control values, respectively, at the 100 mumol/kg dose only. The administration of IMSP at 1, 10 or 100 mumol/kg had no significant effect on hepatic Phase I enzymes activities (cytochrome P-450 concentrations, ethoxycoumarin O-deethylase [ECD] and aminopyrine N-demethylase [AND] activities) or Phase II enzyme activities (GST, QR and UDP-glucuronosyltransferase [UDP-GT] activities towards 1-naphthol or 4-hydroxybiphenyl), at any of the doses tested and no effect on intestinal enzyme activities at doses below 100 mumol IMSP/kg. It is concluded that IMSP does not have a significant influence on induction of the Phase I or Phase II xenobiotic metabolizing enzymes in rats when tested at doses approximating those found in the human diet.
1-Isothiocyanato-3-(methylsulphinyl)-propane (IMSP or iberin) is one of the major glucosinolate hydrolysis products found in cruciferous vegetables. The toxicity of IMSP after oral administration is unknown. This study examined the histological lesions and serum biochemical alterations resulting from intragastric administration of IMSP to male Fischer F344 rats. Rats were administered IMSP in corn oil by gavage at concentrations of 0.1, 0.3, 0.6, 1.0 and 2.0 mmol/kg body weight. Rats were anaesthetized and exsanguinated, and perfusion fixed at 4, 24 and 72 hr after dosing. IMSP caused a dose-dependent decrease in body weight for the first 24 hr after dosing. Multifocal haemorrhages and erosions of the mucosal portion of the stomach were grossly and histologically evident after 4 hr in rats dosed with more than 0.3 mmol IMSP/kg body weight, with severity increasing with dose. Mucosal lesions resolved by 72 hr in all but the 2 mmol/kg group. No significant lesions were observed in the liver or kidney. No physiologically significant haematocrit, electrolyte, blood urea nitrogen, creatinine or serum enzyme activity changes were observed. Urine collected after a dose of 1 mmol IMSP/kg body weight accounted for 1% of the IMSP, demonstrating that the compound was absorbed from the gastro-intestinal tract.
In this study a polymorphism in the conjugating activity of human erythrocyte cytosol towards the dihaloethane, ethylene dibromide (EDB; 1,2-dibromoethane) was found. Two out of 12 human erythrocyte cytosols did not catalyze the formation of glutathione (GSH) conjugates of [1,2-14C]EDB. Ten cytosols formed the S,S'-ethylenebis(GSH) conjugate at a rate ranging from 0.5 to 3.2 (mean 1.76 +/- 0.95) pmol min-1 (mg protein)-1. The activity of the cytosols towards EDB was compared with the activity towards 1,2-epoxy-3-(p-nitrophenoxy)-propane (EPNP) and 1-chloro-2,4-dinitrobenzene (CDNB). The GSH conjugates formed from EDB, EPNP and CDNB were all quantified by HPLC. Every cytosol was active with the classical GST substrate CDNB (2.04 +/- 0.74 nmol min-1 (mg protein)-1). The two samples not showing any detectable activity towards EDB were also inactive towards EPNP: The activity towards EDB correlated significantly with EPNP (rs = 0.90, P < 0.005; Spearman's rank correlation), but not with CDNB (rs = 0.36, P > 0.10). In the incubations with EPNP, the alpha-, mu-, and pi- class glutathione S-transferase (GST) inhibitor S-hexyl(GSH) was included, indicating that the class-theta GST is the principal GST class conjugating EDB in erythrocyte cytosol. The apparent polymorphism of GST-theta which has recently been recognized to be crucial for several mono- and dihalomethanes, will thus also have considerable implications for the risk assessment of EDB.
Genotoxicological investigation of 1,3-propane sultone was undertaken using human lymphocyte cultures as the test system. Concentrations greater than 1 mM induced appreciable chromosomal aberrations, which increased proportionally to the dose or the duration of treatment. It was also observed that treatment administered at 45 degrees C produced almost 3 times more abnormal cells than at 37 degrees C. The chemical also produced a significantly higher frequency of SCEs.
A sensitive and selective high-performance liquid chromatographic (HPLC) method was developed for the determination of 1,3-di(4-imidazolino-2-methoxyphenoxy)propane (DMP) in rat, dog and human plasma (50-5000 ng/ml) and urine (0.1-10 micrograms/ml). DMP and DMPent (dimethoxyimidizolinopentamidine, the internal standard), are extracted from alkanized plasma with n-butyl chloride-n-butanol (9:1, v/v). The organic phase is dried under nitrogen, reconstituted in mobile phase, and washed with hexane. Separation is achieved by ion-pair chromatography on a Zorbax Rx C8 column with fluorescence detection. The analysis of pooled plasma (80, 400, and 4000 ng/ml) and urine controls (0.3, 1.6, and 8 micrograms/ml) demonstrated excellent precision and accuracy over a three-day period. The recovery of DMP is > 90% from rat, dog, and human plasma and > 85% from rat and human urine, and 60-70% from dog urine. The limit of quantitation (LOQ) of the assay is 50 ng/ml in rat, dog and human plasma. Using the high-sensitivity assay, the limit of quantitation was decreased to 5, 2 and 0.6 ng/ml in rat, dog and human plasma, respectively. The LOQ of the assay is 0.1 microgram/ml in rat, dog and human urine. The assay was used to determine plasma and urine concentrations of DMP in pharmacokinetic studies in rat and dog.
A zwitterionic surfactant, N-dodecyl-N,N-dimethylammonium-3-propane-1- sulfonic acid (SB-12), was used in combination with an anionic surfactant, sodium dodecyl sulfate (SDS), to form a novel pseudostationary phase for use in micellar electrokinetic chromatography. This mixed micellar system was characterized in terms of analyte retention, selectivity, efficiency, elution range, and resolution; and compared to results obtained using only SDS. A typically used SDS concentration, 20 mM, was chosen as a reference to which comparisons could be drawn. With 20 mM SDS, the optimum concentration range of 10-20 mM SB-12 provided efficiencies that were 2-4 times greater than with SDS alone, with minimal (< 15%) changes in the elution range and electroosmotic flow. The addition of 40 and 60 mM SB-12 also resulted in efficiencies on average of 600,000-800,000 theoretical plates/m, but at a significant reduction in the elution range and peak capacity. Retention factors (k') for the various neutral analytes increased by 20% with addition of 10 mM SB-12 and by approximately 60% with addition of 40 and 60 mM SB-12, while operating currents remained constant as SB-12 was added. Geometrical isomers p-nitrotoluene and m-nitrotoluene, that co-eluted with 20 mM SDS, were baseline resolved with the addition of 10 mM SB-12; in addition, methylene selectivity was greatest at this composition. No capillary wall interactions or coating effects were observed with the SDS-SB-12 mixed micellar system, in contrast to previously studied anionic-non-ionic mixed micellar system, SDS-Brij 35. Consequently, migration times were very repeatable (< or = 1.2% R.S.D.).
Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane, 5 (4-HIPP), was synthesized and evaluated as a simple vesamicol-like radiotracer for mapping cholinergic pathways in the brain. Both enantiomers of 5 exhibit significant accumulation (approx. 2% of injected dose) and prolonged retention (t1/2 greater than 3 h) within the rat brain. The accumulation of radioiodinated 5 in the rat brain was reduced by up to 70% in the presence of vesamicol and its analogs. The levorotary isomer (-)-4-[123I]HIPP exhibits significant accumulation in the monkey brain, with a half-life of about 9 h. Radioiodinated 5 may therefore be a useful tool for studying cholinergic pathways in the brain.
3-Amino-2-hydroxy-propionaldehydes [H2NCH(R)CHOHCHO with R = H, i-Bu, CH2Ph] were designed as metallo-aminopeptidase inhibitors based on the metal active site chelation concept. These compounds were found to be micromolar inhibitors of aminopeptidase-M (AP-M, EC 3.4.11.2) with potencies similar to bestatin (Ki = 3.5 microM). Notably, compound 5a (R = H) is a selective inhibitor of AP-M (Ki = 7 microM) with respect to cytosolic leucine aminopeptidase (LAPc, EC 3.4.11.1) (Ki = 385 microM). However, due to their easy oligomerization, these compounds are low practical value. In contrast, the corresponding isomeric 3-amino-1-hydroxy-propan-2-one derivatives [H2NCH(R)COCH2OH with R = H, i-Bu, CH2Ph, i-Pr, CH2Biph] are well defined structures. These hydroxymethylketones also exhibit micromolar affinities on AP-M. Compound 6c (R = CH2Ph) was the most potent (Ki = 1 microM). Selectivity studies of 6a (R = H) and 6b (R=i-Bu) show a preference for AP-M. Compound 6a is moderately active on AP-M (Ki = 25 microM) and inactive on LAPc. This new class of inhibitors is proposed to bind as bidentates, analogous to hydroxamates.