Potent suppressive effects of 3-O-methylquercetin 5,7,3',4'-O-tetraacetate on ovalbumin-induced airway hyperresponsiveness

We investigated the suppressive effects of 3-O-methylquercetin 5,7,3',4'- O-tetraacetate (QMTA), a more-potent phosphodiesterase (PDE)3/4 inhibitor than quercetin 3-O-methyl ether (3-MQ), which has been reported to have the potential for treating asthma, against ovalbumin (OVA)-induced airway hyperresponsiveness (AHR). The IC50 value of QMTA for PDE3 was significantly less than that for PDE4. According to the Lineweaver-Burk analysis, QMTA (1-10 microM) competitively inhibited PDE3 and PDE4 activities. The Ki values were 0.9+/-0.3 (n=5) and 3.9+/-0.5 (n=5) microM, respectively, which significantly differed from each other, suggesting that QMTA has higher affinity for PDE3 than for PDE4. QMTA (3-10 microM) concentration-dependently relaxed the baseline level, and significantly inhibited cumulative OVA (10-100 microg/mL)-induced contractions in isolated sensitized guinea pig trachealis suggesting that QMTA has bronchodilator and inhibiting effects on mast cell degranulation. After the secondary challenge, the AHR was measured in unrestrained OVA-sensitized mice, with nebulized methacholine (MCh, 6.25-50 mg/mL), by barometric plethysmography using a whole-body plethysmograph. In the present results, QMTA (3-10 micromol/kg, I. P.) dose-dependently attenuated the enhanced pause (Penh) value induced by MCh (25-50 mg/mL). QMTA (3-10 micromol/kg, I. P.) also significantly inhibited total inflammatory cells, macrophages, neutrophils, lymphocytes, and eosinophils in BALF after determination of Penh values. It also significantly suppressed the release of interleukin (IL)-2, IL-4, IL-5, IFN-gamma, and TNF-alpha, with the exception that 3 micromol/kg QMTA did not suppress the releases of IL-5. QMTA even at 1 micromol/kg significantly inhibited eosinophils, IL-2, and TNF-alpha. In conclusion, our results strongly suggest that QMTA has greater potential than 3-MQ for the treatment of asthma.     

The mutagenic, DNA-damaging and antioxidative properties of bark and leaf extracts from Coutarea hexandra (Jacq.) K. Schum

Coutarea hexandra is a species commonly known in Brazil as quina, and its bark is used in folk medicine. In this study, we assess the mutagenic and DNA-damaging effects of ethanol extracts from C. hexandra stem bark (SCH) and leaves (LCH) by employing the Ames test on the TA98 and TA100 strains of Salmonella typhimurium in addition to a plasmid treatment test. Furthermore, we performed a phytochemical analysis by TLC and HPLC, a quantification of the phenolic constituents and an assessment of the antioxidative activity. SCH and LCH showed mutagenic action in the Ames test for TA98 strains after metabolic activation. LCH also showed mutagenicity for the TA100 strain after metabolic activation. The findings from the plasmid treatment test did not indicate any DNA-damaging activity for either of the extracts with the tested dosages. SCH showed greater flavonoid content and greater antioxidative potential in relation to LCH. This study suggests that caution is advisable in the use of this plant. However, in vivo studies should be conducted to confirm these data.     

Synthesis and complement inhibitory activity of B/C/D-ring analogues of the fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy- 2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran

This paper reports the synthesis and the bioassay of 4-methoxy- and 4-hydroxyspiro[benzofuran-2(3H)-cyclohexane] partial analogues (5) of the complement inhibitory sesquiterpene fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy-2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a, K-76) and its silver oxide oxidized product (1b, K-76COOH). The described target compounds represent spirobenzofuran B/C/D-ring analogues lacking the A-ring component of the prototype structure. The target compounds were evaluated by the inhibition of total hemolytic complement activity in human serum. It was observed that the structurally simplified analogue 4-methoxyspiro[benzofuran-2(3H)-cyclohexane]-6-carboxylic acid (5a) exhibited an IC(50) = 0.53 mM similar to the IC(50) = 0.57 mM that was observed for the natural product derivative 1b. Exhibiting an IC(50) = 0.16 mM, the three-ringed partial structure 6-carboxy-7-formyl-4-methoxyspiro[benzofuran-2(3H)-cyclohexane] (5k)was found to be the most potent target compound. Like the natural product, 5k appears to inhibit primarily at the C5 activation step and inhibits both the classical and alternative human complement pathways. Several other analogues inhibited complement activation in vitro at concentrations similar to those required for inhibition by the natural product 1b.     

A new flavone glycoside: 5,7,3',4'-tetrahydroxy-3-methoxy flavone-7-O-beta-D-galactopyranosyl-(1-->4)-O-beta-D-glucopyranoside from the stem of Acacia catechu Willd

A new bio-active flavone glycoside, m.p. C 28 H 32 O 17 , mp 283-284°C, M + 640 [EIMS] was isolated from the ethylacetate soluble fraction of the ethanolic extract of the stems of Acacia catechu and its structure was characterised as 5,7,3',4'-tetrahydroxy-3-methoxy flavone-7- O - β- d -galactopyranosyl-(1 →4)- O - β- d -glucopyranoside by various chemical degradations and spectral analyses.     

The gastric antisecretory activity of 3-methoxy-5,7,3'4'-tetrahydroxyflavan (ME)--a specific histidine decarboxylase inhibitor in rats

3-Methoxy-5,7,3'4'-tetrahydroxyflavan (ME), a specific histidine decarboxylase inhibitor, has been shown to significantly reduce the gastric acid secretion and gastric tissue histamine levels in 6 h pylorus ligated rats. It has been found to be as effective as cimetidine in reducing the gastric acid secretion. However, cimetidine does not affect the gastric tissues histamine levels in the normal or pylorus ligated rats. These observations clearly establish that the two drugs reduce the gastric acid secretion by different mechanisms and suggest that their combination may show a potentiated gastric anti-ulcer activity.     

Toxicity of 3,4,5,3',4',5'-hexabrominated biphenyl and 3,4,3',4'-tetrabrominated biphenyl

Immature male rats were given a single equimolar dose (21.3 mumol/kg body wt) of 3,4,5,3',4',5'-hexabromobiphenyl (HBB) or 3,4,3',4'-tetrabromobiphenyl (TBB) and terminated at various times up to 14 days after treatment. Hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity for the TBB treatment group was maximal at Day 2 and then steadily decreased, whereas this activity was induced in 1 day and remained high for the HBB treatment group. Tissue concentrations of HBB appeared to be unchanged over time whereas tissue concentrations of TBB decreased in a biphasic manner. Rates of in vitro metabolism of TBB with hepatic microsomes from TBB-treated animals showed a similar time-course relationship to AHH induction. HBB caused moderate to severe hepatic changes while TBB-treated rats had only mild hepatic changes. The relative binding of TBB by the hepatic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was about 10 times that of HBB. The results suggest that even though the receptor-binding affinities imply that TBB should be more toxic than HBB, it is less toxic than HBB because it is metabolized. Studies with the chlorinated analogs of TBB and HBB suggested that PCB behave similarly. These results also suggest that receptor binding and AHH induction do not accurately reflect toxicity for polyhalogenated aromatic hydrocarbons which are metabolized, presumably because continued occupation of the receptor and persistent induction of some enzyme activity are required for toxicity.     

Characterization of the Photolysis of 2,4,5,2',4',5'-Hexabromobiphenyl

Characterization of the Photolysis of 2,4,5,2',4',5'-Hexabromobiphenyl.MILLIS, C. D., AND AUST, S. D. (1985). Fundam. Appl. Toxicol.5, 546–554. 2,4,5,2',4',5'-Hexabromobiphenyl (2,4,5-HBB)was irradiated with ultraviolet light in hexane with stirring,and photolysis was monitored by gas chromatography (GC). 2,4,5-HBBdecomposed at an average rate of 0.66±0.02 µmol/minand the reaction appeared zero order from 0.159 to 1.59 mM 2,4,5-HBB.Several polybrominated biphenyl (PBB) congeners were identifiedas photoproducts of 2,4,5-HBB. 2,4,5,2',5'-Pentabromobiphenyl(-PBB), formed by para debromination, accumulated at a higherrate than did 2,4,5,3',4'-PBB, formed by ortho debromination.2,4,5,2',4'-PBB was formed by meta debromination. 3,4,3',4'-Tetrabromobiphenyl(-TBB) was found as a secondary photoproduct, formed by orthodebromination of 2,4,5,3',4'-PBB. 2,5,2',5'-TBB and 2,4,2',5'-TBBwere formed by debromination of 2,4,5,2',5'-PBB para and meta,respectively. 2,5,3',4'-TBB could be formed by either orthodebromination of 2,4,5,2',5'-PBB or para debromination of 2,4,5,3',4'-PBB.Rates of degradation and accumulation of the penta- and tetrabrominatedbiphenyls were also studied. The ultraviolet spectra of the2,4,5-HBB photolysis mixture, as well as the purified components,were studied and are also reported     

Synthesis of New 2-Substituted 6-Hydroxy-8-azapurines (8-Azahypoxanthines)

Pharmaceutical Chemistry Journal -     

Metabolite of 2,2',4',5-tetrabromobiphenyl, 3-methylsulphonyl-2,2',4',5-tetrabromobiphenyl,a potent inducer of CYP2B1/2 in rat

1. 3-Methylsulphonyl- and 4-methylsulphonyl-2,2',4',5-tetrabromobiphenyls (3-MeSO(2)- and 4-MeSO(2)-TetraBrBs) were detected in the liver, lung, kidney, adipose tissue and faeces of the 2,2',4',5-tetrabromobiphenyl (TetraBrB)-dosed rat. 2. The administration of 0.05-2.0 micromol kg(-1) doses of 3-MeSO(2)-TetraBrB produced corrresponding increases in the hepatic concentration of the methyl sulphone metabolite, corresponding increases in the content of total cytochrome P450, and corresponding increases in the activities of 7-benzyloxy-, 7-ethoxy- and 7-pentoxyresorufin O-dealkylases. The inducing effects of the 3-MeSO(2)-TetraBrB (0.2 micromol kg(-1)), both on the content of total P450 and on the activities of the three alkoxyresorufin O-dealkylases, were higher than that of the parent TetraBrB (342 micromol kg(-1)). 3. The major phenobarbital (PB)-inducible forms of P450, CYP2B1, CYP2B2, CYP3A2 and CYP2C6, were substantially induced by 3-MeSO(2)-TetraBrB, but CYP1A1 and CYP1A2 were not. On the other hand, the activities of drug-metabolizing enzymes and the four PB-inducible forms of P450 were unchanged by 4-MeSO(2)-TetraBrB treatment. 4. The induction profiles of these enzymes and P450 forms in rat treated with 3-MeSO(2)-TetraBrB were similar to those treated with PB. 5. The inducing ability of 3-MeSO(2)-TetraBrB (0.5 micromol kg(-1)) both on the activities of the three alkoxyresorufin O-dealkylases and on the contents of four PB-inducible forms of P450 was roughly equal to that of PB (431 micromol kg(-1) twice at a 24-h interval) or 3-MeSO(2)-2,2',4',5-tetrachlorobiphenyl (1 micromol kg(-1)). It is noteworthy that the effects of 3-MeSO(2)-TetraBrB on the drug-metabolizing enzymes CYP2B1 and CYP2B2 were several thousand-fold higher than those of parent TetraBrB, while the effect of its isomeric 4-MeSO(2)-TetraBrB were not. 6. The extent of hepatic accumulation of the 3-MeSO(2) metabolite after the administration of TetraBrB (342 micromol kg(-1)) was almost the same as that after the administration of 3-MeSO(2)-TetraBrB (0.1-0.2 micromol kg(-1)). The relationship between the hepatic concentration of the 3-MeSO(2) metabolite and the extent of enzyme induction after the administration of TetraBrB or 3-MeSO(2)-TetraBrB suggests that 3-MeSO(2)-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.     

Transport of 2,4,5,2',4',5'-hexachlorobiphenyl by lipoproteins in vivo

Lipoproteins are currently being recognized as transport vehicles for lipophilic drugs and xenobiotic chemicals in plasma. The weight of in vitro evidence suggests lipoproteins as the principal carries of 2,4,5, 2',4',5'-hexachlorobiphenyl (6-CB) in plasma from normolipidemic rats and humans. The present study examined the in vivo distribution of 6-CB among lipoproteins as well as the influence of time on the absolute amount and proportion of 6-CB associated with each density fraction. Plasma obtained between 1 min and 24 hr after an iv injection of 6-[14C]CB was separated into very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions by sequential ultracentrifugation. The in vivo results corroborate the in vitro data which suggest LDL to be a major transport vehicle for 6-CB in plasma. However, the preference of 6-CB for LDL existed for only a short time following injection. From 6 to 24 hr after administration of 6-CB, there was a shift in the distribution of the PCB from LDL to HDL and the remaining protein-rich bottom fraction. By 24 hr, the proportion of 6-CB in LDL had declined from 80% of the plasma concentration to 30%, while that in HDL had doubled. Furthermore, the amount of 6-CB in the bottom fraction accounted for 35% of the radioactivity in plasma at 24 hr as opposed to less than 5% up to 1 hr after administration. The absolute contents of 6-CB in both HDL and the bottom fraction also increased during the later time points. Analysis of the decay curves of 6-CB among the various lipoproteins further substantiated a change in the distribution of 6-CB over time. The decay of 6-CB in LDL most closely resembled its disappearance from plasma. The content of 6-CB remaining in plasma at 24 hr was equally distributed among LDL, HDL, and the bottom fraction. Changes in lipoprotein composition during the 24-hr period could not explain 6-CB redistribution, since there were no significant differences in the proportion of constituents comprising VLDL, LDL, HDL, or the bottom fraction.