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101.
Oxotremorine antagonism by prolyl-leucyl-glycine-amide administered by different routes and with several anticholinergics 总被引:3,自引:0,他引:3
Prolyl-leucyl-glycine amide (PLG) was given by oral, intravenous, or subcutaneous routes of administration and shown to antagonize the central and peripheral effects of oxotremorine. The previously demonstrated action of PLG in this system when injected intraperitoneally in a single dose was found to be unchanged when administered by the same route for five consecutive days. Although three anticholinergic compounds were also effective in reducing the effects of oxotremorine, no interactions between PLG and trihexyphenidyl hydrochloride, benzotropin mesylate, or scopolamine were observed. The results confirm and extend the demonstration of the extra-endocrine effects of PLG. 相似文献
102.
The quantitative relationship between the ability of polycyclic aromatic hydrocarbons to repress the mixed-function oxidase, dimethylnitrosamine-demethylase, and a parameter expressing the shape of the hydrocarbon molecules, has been studied. The shape parameter represents the ratio of the longer to shorter sides of the minimum rectangular envelope around the structure, drawn proportionally to atomic dimensions. The shape parameter allows the prediction of the relative biological activity of 23 active and 4 inactive compounds. 相似文献
103.
Aryl hydrocarbon hydroxylase (AHH) has been measured in male rat liver nuclei and microsomes after treatment of adult animals with various inducers for up to 14 days. After daily i.p. injections of 3-methylcholanthrene (MC, 20 mg/kg) the nuclear activity increased to a maximum of 600 per cent of the control activity after 4 days whereas the microsomal activity was 400 per cent of control at the same date. After 12 days, both activities equilibrated at 400 per cent. A similar time course was found after a single i.p. injection of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD, 0.01 mg/kg) with an induction to 500 and 300 per cent for nuclei and microsomes, respectively, after 2 days, and to 400 per cent for both after 12 days. Phenobarbital (PB) was given continuously in the drinking water (1 g/l) and induced the microsomal activity to 200 per cent after 8 days and 170 per cent after 14 days. the nuclear activity was only slightly induced to a Constant level of 130 per cent between day 8 and 14. Dieldrin did not significantly increase the microsomal activity after daily i.p. injections (20 mg/kg), but the nuclear activity raised to 200 per cent after 3 days and levelled down to control values after 12 days. Other inducers tested were benz[a]anthracene (BA), hexachlorobenzene (HCB) and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). The induction pattern with BA was similar to that of MC, a model compound for the group of cytochrome P448 inducers. the induction by HCB and DDT resembled that by PB, a typical cytochrome P450 inducer. 相似文献
104.
The polycyclic aromatic hydrocarbon, benzo[a]pyrene, induced dose-related nuclear damage (micronuclei, pyknotic nuclei and karyorrhectic bodies) in colonic epithelial cells of C57BL/6J mice within 24 hr when administered intrarectally in single doses of 0-200 mg/kg body weight. This damage was reduced when mice ingested the plant phenols, caffeic, ferulic and ellagic acids, and quercetin at levels of 4% or BHA at 2% (w/w) in the diet for 1 wk prior to the benzo[a]pyrene challenge (100 mg/kg body weight). Benzo[a]pyrene-induced nuclear damage was not significantly inhibited by 4% curcumin under similar conditions. The inhibition of nuclear damage is consistent with reported antimutagenic effects for these agents in vitro and in longer term animal studies. The procedure described here may provide a rapid in vivo method for assessing the potential of natural products to inhibit the carcinogenic process. 相似文献
105.
Fowler CJ Tiger G Ligresti A López-Rodríguez ML Di Marzo V 《European journal of pharmacology》2004,492(1):1-11
There is considerable debate at present as to whether the uptake of anandamide (AEA) into cells is by a facilitated transport process or by passive diffusion driven by fatty acid amide hydrolase (FAAH). The possibility that both processes occur, but to different extents depending upon the cell type used, has been difficult to investigate pharmacologically since available compounds show little selectivity between inhibition of AEA uptake and inhibition of FAAH. Recently, three compounds, UCM707 [N-(Fur-3-ylmethyl)arachidonamide], OMDM-1 and OMDM-2 [the 1'-(S)- and 1'-(R)-enantiomers of the 1'-4-hydroxybenzoyl analogue of oleoylethanolamide], selective for the uptake process, have been described and we have used these compounds, together with AM404 [(N-(4-hydroxyphenyl) arachidonoyl amide)] and VDM11 [(5Z,8Z,11Z,14Z)-N-(4-Hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide]), with the initial aim of determining which mechanism of uptake predominates in C6 glioma and RBL-2H3 cells. AM404 and VDM11 were both found to decrease the uptake of 2 microM AEA into cells (IC50 values 6-11 microM), but they also inhibited rat brain FAAH (IC50 values 1-6 microM). However, when using a different FAAH assay protocol, VDM11 was a much less potent FAAH inhibitor (IC50>50 microM) regardless of the cell type and animal species used. In contrast, we confirmed that UCM707, OMDM-1 and OMDM-2 were weak inhibitors of FAAH (IC50 values >50 microM) under all conditions used. However, their potency as inhibitors of AEA cellular accumulation appears to be largely dependent on the cell type and assay conditions used. In particular, the potency of UCM707 (IC50 value > or =25 microM) was considerably lower than the submicromolar potency previously reported for U937 cells. It is concluded that the cause/effect relationship between AEA uptake and hydrolysis cannot be investigated uniquely by using supposedly selective inhibitors of each process. 相似文献
106.
Induction of cytochrome P450 (CYP1A), as measured by liver ethoxyresorufin-O-deethylase (EROD) activity in juvenile rainbow trout (Oncorhynchus mykiss), was used to derive relative potency factors (RPFs) for several polycyclic aromatic hydrocarbons (PAHs), chosen for their induction potency in a rainbow trout liver cell line (RTL-W1). Potency for causing induction was estimated as the median effective concentration (EC50) from exposure-response curves. With the exception of phenanthrene, all PAHs tested induced EROD activity in juvenile trout, ranked as: benzo[k]fluoranthene>benzo[b]fluoranthene>benzo[b]fluorene>beta-napthoflavone>retene (7-isopropyl-1-methylphenanthrene). When induction potency was expressed relative to benzo[k]fluoranthene, RPFs ranged from 0.02 to 1, and the rank order in vivo was identical to the rank order with RTL-W1-derived values. The additivity of PAHs in mixtures in RTL-W1 cells was compared to whole-fish results from a previous study. EROD induction showed additive interactions for PAHs with exposure-response curves of similar slopes. This study demonstrates that assays of CYP1A induction using rainbow trout liver cells in culture would be a convenient substitute for assays with whole fish as part of testing programs for risk assessment of PAHs. 相似文献
107.
Kim JY Lee SK Kim CH Jeon TW Moon CK Lee HS Yoo SD Lee ES Jeong TC 《Archives of pharmacal research》2003,26(5):394-404
Certain polycyclic aromatic hydrocarbons (PAHs) have been reported to induce cytochrome P450 (CYP) 1A1 and 1A2. In the present study, the effects of six well-known PAHs, such as benzo[a]pyrene, benz[a]anthracene, dibenz[a,h]anthracene, chrysene, benzo[k]fluorancene and benzo[b]fluorancene, on the activities of hepatic and pulmonary CYP enzymes were investigated in male ICR mice. When mice were treated intraperitoneally with 3, 10 and 30 mg/kg of individual PAHs for 3 consecutive days, the activities of ethoxyresorufin- and methoxyresorufin-O-dealkylases were significantly and differentially induced in both liver and lung. Moreover, other CYP isozyme-associated monooxygenase activities were also induced significantly in liver and lung with characteristic induction profiles. Our present results suggest that individual PAHs might have inductive effects on CYP isozymes, and that the characteristic inductive effects of individual PAHs on certain CYP isozymes would be developed as a marker for determining exposure to certain PAHs. 相似文献
108.
Pietsch EC Hurley AL Scott EE Duckworth BP Welker ME Leone-Kabler S Townsend AJ Torti FM Torti SV 《Biochemical pharmacology》2003,65(8):1261-1269
Compounds that induce the synthesis of cytoprotective phase II enzymes have shown promise as cancer chemopreventive agents. Although chemically diverse, phase II enzyme inducers are capable of participating in Michael reaction chemistry. We have synthesized a novel class of organosulfur compounds, termed oxathiolene oxides (OTEOs). Based on their chemical properties, we hypothesized that these compounds could function as phase II enzyme inducers. Northern blot analysis showed that oxathiolene oxides induce the phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and ferritin H and L mRNA in a concentration-dependent fashion in a normal embryonic mouse liver cell line, BNLCL.2. OTEO-562 (3-cyclohexenyl-4-methyl-1,2-oxathiol-3-ene-2-oxide) was the strongest inducer. Western blot analysis demonstrated that GST-alpha and ferritin H protein levels were also induced in cells treated with OTEO-562, as was total GST and NQO1 enzyme activity. Further, induction of NQO1 activity by OTEO-562 was equivalent in aromatic hydrocarbon (Ah) receptor wild-type and Ah receptor mutant cell lines, suggesting that oxathiolene oxides activate phase II enzymes by an Ah receptor-independent mechanism. Consistent with this observation, OTEO-562 failed to induce cytochrome P450 1A1 mRNA. These results suggest that oxathiolene oxides may merit further investigation as candidate chemopreventive agents. 相似文献
109.
Shimada T Sugie A Shindo M Nakajima T Azuma E Hashimoto M Inoue K 《Toxicology and applied pharmacology》2003,187(1):1-10
Tissue-specific induction of mRNA of cytochrome P450 (P450 or CYP) 1A1 and 1B1 by polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) was investigated in wild and arylhydrocarbon receptor (AhR)-deficient C57BL/6J mice. Ratios of mRNA expression of CYP1A1 or CYP1B1 over beta-actin were determined and used to compare levels of expression and induction of these P450s by PAHs and PCBs in various organs. CYP1A1 mRNA was detected in control mice at very low levels in liver, lung, heart, kidney, intestine, thymus, testis, uterus, ovary, and brain and was highly induced in these organs by benzo[a]pyrene and 3,4,3',4'-tetrachlorobiphenyl in AhR(+/+) mice. In AhR(+/+) and AhR(-/-) mice, CYP1B1 mRNA was found to be constitutively expressed at significant levels in heart (the ratio of mRNAs of CYP1B1 to beta-actin was approximately 0.6), kidney ( approximately 0.8), intestine ( approximately 0.3), testis ( approximately 0.9), thymus ( approximately 0.4), uterus ( approximately 0.3), ovary ( approximately 1.4), and brain ( approximately 0.4), whereas it was low in liver and lung (the mRNA ratio to beta-actin was <0.2 in these cases). CYP1B1 in the latter two organs was highly induced by PAHs and 3,4,3',4'-tetrachlorobiphenyl in AhR(+/+) mice. The induction of CYP1B1 by PAHs and PCBs was more extensive in organs in which the constitutive expression of CYP1B1 was low. For example, CYP1B1 was induced 9-fold and 10-fold by benzo[a]pyrene and 3,4,3',4'-tetrachlorobiphenyl in livers of male and female mice, respectively, whereas in testis and ovary, the fold induction of CYP1B1 by two inducers was only 1.1 and 1.4, respectively. Liver microsomal xenobiotic oxidation activities were induced by these PAHs and PCBs in male and female AhR(+/+) mice. These results suggest that CYP1A1 and CYP1B1 are differentially regulated in their expression in extrahepatic organs of mice and could be induced by PAHs and PCBs with different extents of induction depending on the inducers used and the organs examined in AhR(+/+) mice. The findings of significant levels of constitutive expression of CYP1B1 in AhR(-/-) mice as well as AhR(+/+) mice in several organs including heart, kidney, thymus, testis, ovary, and brain in AhR(-/-) mice as well as AhR(+/+) mice are of importance in understanding the basis of toxicity and carcinogenesis by chemicals that are metabolized by CYP1B1. 相似文献
110.