Distribution and excretion of 2,3,6,2′,3′,6′- and 2,4,5,2′,4′,5′-hexachlorobiphenyl in senescent rats

The disposition of two symmetrical [¹⁴C]hexachlorobiphenyls (HCBs), 2,3,6,2′,3′,6′-HCB (236) and 2,4,5,2′,4′,5′-HCB (245), was studied in 24-month-old male Sprague-Dawley rats after iv treatment. Because body composition changes with age, complete dissections were performed on all rats to determine the size of the skin and adipose tissue depots. More than 50% of 236 was metabolized and excreted via the bile into the feces within 2 days. In contrast, 245 redistributed from the liver, muscle, and skin to adipose tissue where it accumulated without being metabolized. Only 2% of the total dose of 245 was excreted primarily in the feces within 21 days. The data obtained in this study were compared to results previously obtained from 2- to 3-month-old rats in this laboratory (Matthews and Tuey, 1980, Toxicol. Appl. Pharmacol.53, 377–388). Although the general pattern of HCB disposition did not change with age, i.e., metabolism and excretion of 236 versus persistence of 245, there were differences in the rates of elimination and in the tissue levels. There was enhanced metabolite retention in the muscle, skin, and adipose tissue of older animals which suggested an age-related decrease in tissue clearance. The large volume of adipose tissue in these older Sprague-Dawley rats could in part explain this observation. In general, there were few changes in decay rates from tissues or in biliary excretion. Age had a greater effect on the disposition of the persistent 245 than on the metabolizable 236. Thus, changes in body composition seemed to play a major role in age-related changes in the distribution and excretion of polychlorinated biphenyls.     

Synthesis and studies on antidepressant activity of 2′,4′,6′-trihydroxychalcone derivatives

In this study, we synthesized a series of 2′,4′,6′-trihydroxychalcone derivatives and evaluated their antidepressant activities. The results of the nine compounds showed significantly reduced times during the forced swimming test at a dose of 10?mg/kg, indicative of antidepressant activity. Among the compounds, 2-bromo-2′,4′,6′-trihydroxychalcone (3h) was found to be the most potent, and it was observed that compound 3h at dose of 10, 20, and 40?mg/kg significantly reduced the duration of immobility times in the FST and TST in mice 30?min after treatment.     

Synthesis and biological evaluation of novel 2′,4′,5′-trimethoxyflavonol derivatives as anti-inflammatory and antimicrobial agents

A series of novel 3-hydroxy-2-(2,4,5-trimethoxyphenyl)-4H-chromen-4-one (flavonol) derivatives (2a–u) of biological interest have been prepared via CLAISEN–SCHMIDT condensation followed by ALGAR–FLYNN–OYAMADA reaction and to search for the potent nonsteroidal anti-inflammatory agents from this novel series. All the synthesized compounds have been screened for their in vitro proinflammatory cytokines tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) inhibitory activity along with antimicrobial activity. As many as three compounds viz. 2h, 2l, and 2q from this novel series were found to be potent TNF-α and IL-6 inhibitor (up to 72–81 % TNF-α and 86–92 % IL-6 inhibitory activity) but at 10 μM concentration as compared with the standard dexamethasone (71 % TNF-α and 84 % IL-6 inhibitory activities at 1 μM concentration). While the compounds 2d, 2m, 2n, and 2s were found to be potent antimicrobial agent showing even 2–2.5-fold more potency than that of standard ciprofloxacin and miconazole at the same MIC value of 10 μg/mL.     

Disposition of 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine in mice

Summary Mice were dosed with [³H]2,3-dideoxyadenosine ([³H]ddA) in three procedures: intravenously, intraperitoneally, and interperitoneally following a dose of 2 -deoxycoformycin (dCF). For mice dosed intravenously, the content of radioactivity in plasma and tissue samples were essentially constant after 30 min. Of the radioactivity in plasma and brain samples collected between 30 min and 24 hr, more than 94% was present as ³H₂O, indicating that most of the tritium from [³H]ddA had exchanged with water. No intact ddA was detected, and the deamination product, 2,3 -dideoxyinosine (ddI), was present only transiently. In the urine, the major radioactive material was [³H]ddI. Also detected were ³H₂O and small amounts of [³H]hypoxanthine and [³H]ddA. Following intraperitoneal doses to mice, levels of radioactivity in plasma, liver, and kidney increased to a maximum by 15–30 min after dosing but dropped to essentially constant levels thereafter, again indicating that the tritium had exchanged with water. At 5, 15, and 30 min after dosing, ddI was the major radioactive component in plasma. Only small amounts of ddA were present. When dCF was administered 24 hr prior to intraperitoneal [³H]ddA, levels of radioactivity in plasma, liver, and kidney reached a maximum at 30 to 60 min after dosing and decreased to essentially constant levels thereafter. The dCF transiently inhibited the deamination of ddA to ddI, since, in plasma, [³H]ddA was the main radioactive component at 5 and 15 min after dosing. Comparison of HPLC assays based on radioactivity detection and UV absorbance showed that they were equivalent for measuring ddA and ddI in samples derived from dosed mice. Therefore, exchange of tritium must have occurred at a metabolic step beyond ddI.For mice dosed intravenously and orally with unlabeled ddI, there was evidence of a saturated process. Nevertheless, for the high and low intravenous doses of ddI, the percent of dose excreted in the urine as unchanged drug was the same.     

Design, synthesis and antidepressant activity evaluation 2′-hydroxy-4′,6′-diisoprenyloxychalcone derivatives

In this study, 14 2′-hydroxy-4′,6′-diisoprenyloxychalcone compounds were synthesized and their antidepressant activities were evaluated using the forced swimming test. The pharmacological results showed that six compounds significantly reduced immobility times during the forced swimming test at a dose of 10 mg/kg, indicative of antidepressant activity. Among these, three compounds (4d, 4e, and 4g) exhibited better antidepressant activity, with reduced immobility time by 38.3, 34.0, and 27.4 %, respectively. For explanation of the putative mechanism of action, compounds 4e, 4g were tested in chemical induced models.     

Synthesis and Pharmacological Properties of 1-Aryl-4-(3′4′,5′-trimethoxybenzoyl)piperazines

A series of 1-aryl-4-(3′,4′,5′-trimethoxybenzoyl)piperazines (IIa - IIg) having structures containing 3,4,5-trimethoxybenzoyl fragments were synthesized and characterized. Compounds IIa and IIc - IIg demonstrated weak anxiolytic properties and moderately decreased the spontaneous motor activity in rats. Compound IIb exhibited anxiolytic activity comparable with that of buspirone but, in contrast to this reference drug, increased the motor activity of test animals. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 5, pp. 12 – 14, May, 2005.     

Apoptotic effect of synthetic 2′,4′,5′-trimethoxychalcones in human K562 and Jurkat leukemia cells

In this study, we assessed the cytotoxic effect of synthetic 2′,4′,5′-trimethoxychalcones on the human K562 acute myeloid leukemia cell and human Jurkat acute lymphoid leukemia cell. Compounds 13, 16, 19, and 26 showed low IC₅₀ values (4.10–8.56 μM at 72 h) for both cell lines and did not have a cytotoxic effect on normal human lymphocytes. The mechanism of cell death induced by these compounds involves a decrease in the expression of cell proliferation marker Ki67, suggesting inhibition of cell proliferation. Furthermore, these chalcones reduced mitochondrial potential, decreased Bcl-2 expression, and increased Bax expression, indicating that the mechanism of apoptosis induced by them involves the intrinsic apoptosis pathway. The mechanism of action also involves increase in active caspase-3 and decrease in survivin expression. These results support the chalcones as potential antitumoral agents for further optimization.     

Lipoprotein-mediated transfer of 2,4,5,2′,4′,5′-hexachlorobiphenyl into cultured human cells

1. The very low density, low density and high density lipoproteins (VLDL, LDL, HDL), centrifugally separated from human plasma treated with 2,4,5,2′,4′,5′-hexachloro[¹⁴C]biphenyl (¹⁴C-HCB) contained approximately 50% of the ¹⁴C-HCB.

2. Normal skin fibroblasts were incubated at 4°C or 37°C for varying times with medium containing 10% serum, LDL or HDL labelled with ¹⁴C-HCB. Cellular incorporation of ¹⁴C-HCB from serum was temperature-dependent and occurred mainly during the first 30 minutes. Cellular accumulation of ¹⁴C-HCB from isolated lipoproteins was also rapid and was more efficient from HDL than from LDL or serum. Accumulation from HDL was concentration-dependent and temperature-dependent.

3. The efflux of ¹⁴C-HCB from cells into serum- or lipoprotein-containing medium occurred very rapidly and was most effective in the presence of 20% serum. The order of efficiency in removal of HCB from cells was 20% serum, 50 μg LDL protein/ml, and 120 μg HDL protein/ml. Little or no efflux from cells occurred into serum-free, lipoprotein-free medium.

4. HDL may be involved in the delivery of HCB to cells, a role in contrast to the generally accepted theory that HDL transports lipids from cells.     

Effects of arecoline and cholinesterase inhibitors on cyclic guanosine 3′,5′-monophosphate and adenosine 3′,5′-monophosphate in mouse brain

Summary In mice, Arecoline in vivo dose-dependently increased the cGMP concentrations of the cerebellum and the cerebrum (= parts of cortex, hippocampus, hypothalamus, thalamus, striatum and midbrain) without influencing the cAMP levels. The cholinesterase inhibitors paraoxon and physostigmine caused an elevation only in cerebrum, whereas the cGMP content of the cerebellum even decreased.Pretreatment with atropine prevented the rise in cGMP levels as well as the symptoms of cholinergic stimulation elicited by arecoline or paraoxon. Diazepam reduced cGMP levels below control values and blocked the effect of arecoline, while typical symptoms due to arecoline, e.g., tremor and salivation remained unaffected. The tripeptide prolyl-leucyl-glycinamide (MIF) had no effect on either cGMP values or the peripheral signs of cholinergic stimulation elicited by arecoline.The results show that elevation of cGMP in the central nervous system caused by cholinomimetic agents can be prevented not only by cholinolytics, blocking muscarinic receptors but also by influencing other mechanisms to be discussed.     

Liver tumour promoting activity of 3,4,5,3′,4′-pentachlorobiphenyl and its interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin

This study was undertaken to compare the tumour promoting effects induced by 3,4,5,3′,4′-pentachlorobiphenyl (PCB 126) and 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD). In addition, interactive effects in rats treated with combinations of PCB 126 and TCDD were studied. Partially hepatectomized female Sprague-Dawley rats were initiated with nitrosodiethylamin. After 5 weeks of recovery the promotion treatment started and continued for 20 weeks. The results from the present study demonstrate that PCB 126 elicit approximately 10% of TCDD's tumour promoting activity measured as enhancement of the development of γ-glutamyl-transpeptidase-positive altered heaptic foci in the liver. The factor required for the PCB to match the response of TCDD was adopted as a toxic equivalency factor and was in this case 0.1, which is the same as the factor suggested by Ahlborg et al. (1994).In the groups treated with a mixture of PCB 126 and TCDD the tumour promoting effect indicated an additive response. This result suggests that PCB 126 and TCDD act by the same mechanistical pathway, which in turn, supports that the toxic equivalency factor-concept can be used for TCDD-like tumour promoters.     

Transfer of 2,4,5,2′,4′,5′-hexachlorobiphenyl and 2,2-bis-(p-chlorophenyl),1,1,1-trichloroethane (p,p′-DDT) from maternal to newborn and suckling rats

Pregnant rats were given a small dose of ¹⁴C-2,4,5,2,4,5-hexachloro-biphenyl (HCB) and ³H-DDT intraperitoneally. The transfer of HCB and DDT through the placenta and milk was then investigated. Transfer through the placenta was 2.7 and 1.5% (respectively) of the initial doses; transfer through milk was 39.2 and 21.5%. HCB is obviously more transferable than DDT through the placenta and milk, the ratio of the amount of HCB transferred through milk to the amount transferred through the placenta agrees with that for DDT.Concentrations of HCB and DDT in the whole suckling rat increases rapidly and is similar to the sigmoidal growth curve and change in lipid concentration. Therefore, the concentrations of the chemicals in the maternal tissue generally decrease in comparison with those of nonpregnant rats.     

Protective effects of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone against hydrogen peroxide-induced oxidative stress in hepatic L02 cell

2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC) is a chalcone isolated from the buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry, and the hepatoprotective effects of DMC on Kunming mice have been studied in previous study. However, the effects of DMC on hepatocyte toxicity and corresponding mechanism remain unclear. The aim of this study was to evaluate the hepatoprotective mechanism of DMC in human hepatocytes (L02) treated with H₂O₂. The results demonstrated that pretreatment with DMC effectively protected H₂O₂-induced cell viability loss, cell membrane damage (lactate dehydrogenase, nitric oxide production and caspase-3 accumulation. Besides, DMC pretreatment increased the amount of glutathione, decreased malondialdehyde and the percentage of apoptotic L02 cells compared with only H₂O₂ treated group. Taken together, these results indicated that DMC had hepatoprotective effects against H₂O₂-induced liver injury by alleviating oxidative stress and apoptosis process in L02 cells, and DMC might be a potential candidate for the intervention of liver diseases.     

查尔酮类天然产物2′,4′-二羟基-6′-甲氧基-3′,5′-二甲基查耳酮的研究进展

2′,4′-二羟基-6′-甲氧基-3′,5′-二甲基查耳酮(DMC)是一种来源于多种植物的查尔酮类天然产物,具有良好的药理活性。本文从理化性质、来源、提取与检测、化学合成、药理活性等方面对DMC的国内外研究进展进行综述,为DMC的前药设计和开发提供参考依据。     

Metabolism and presynaptic inhibitory activity of 2′,3′ and 5′-adenine nucleotides in rat vas deferens

Summary In the isolated rat vas deferens stimulated at 0.2 Hz, [¹⁴C]labelled 5-AMP, 5-ADP and 5-ATP (10 M) inhibited twitch responses, were broken down to [¹⁴C]adenosine in the medium and incorporated into [¹⁴C]adenine ribonucleotides in the tissue. Pretreatment of tissues with 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBTGR), a potent inhibitor of adenosine transport, potentiated the presynaptic inhibitory action of these 5 nucleotides and reduced their incorporation in [¹⁴C]adenine nucleotides, but did not alter the appearance of [¹⁴C]adenosine in the medium.A series of 2, 3 and 5-substituted adenine nucleotides (10 M) inhibited the twitch responses of the vas deferens stimulated at 0.2 Hz. This effect was potentiated by NBTGR. Addition of exogenous adenosine deaminase very significantly reduced the inhibitory actions of adenosine, 5-AMP, 5-ADP and 5-ATP and also reduced those of 2, 5-ADP, NAD⁺ and dePCoA. The inhibitory actions of the other 2, 3 and 5 adenine nucleotides studied were not altered by exogenous adenosine deaminase.These results indicated that the presynaptic inhibitory actions of 5-AMP, 5-ADP and 5-ATP in rat vas deferens predominantly result from their prior hydrolysis to adenosine whereas the 2, 3 and 5-substituted adenine nucleotides appear to act mainly directly to inhibit transmitter release.Abbreviations. The following abbreviations are used 5-ADP 5-adenosine diphosphate - 2,5-ADP 2,5-adenosine diphosphate - 3,5-ADP 3,5-adenosine diphosphate - 2,3 or 5-AMP 2,3 or 5-adenosine monophosphate - 5-ATP 5-adenosine triphosphate - CoA coenzyme A - 2,3-cAMP 2,3-cyclic adenosine monophosphate - cNADP⁺ -nicotinamide dinucleotide 2,3-cyclic monophosphate - dePCoA dephosphocoenzyme A - NAD⁺ -nicotinamide adenine dinucleotide - NADP⁺ -nicotinamide adenine dinucleotide phosphate - NBTGR 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine - oxid CoA oxidized-coenzyme A