Prevention of chromosomal aberration in mouse bone marrow by indole-3-carbinol.

In this study, we report the protective effect of indole-3-carbinol (I3C), one of the glucobrassicin derivative isolated from cruciferous vegetables against cyclophosphamide induced chromosomal aberrations in mouse bone marrow cells. The three test doses namely 1000,500 and 250 mg/kg b.wt. of I3C provided protection when given 48 h prior to the single i.p. administration of cyclophosphamide (50 mg/kg). I3C alone did not induce chromosomal aberrations at the test doses of 1000 and 500 mg/kg b.wt.. Thus tested glucobrassicin derivative seems to have a preventive potential against cyclophosphamide induced chromosomal aberrations in Swiss mouse bone marrow cells at the doses tested.     

Protective effect of Cassia occidentalis extract on chemical-induced chromosomal aberrations in mice.

This study was conducted to determine the antimutagenic potential of aqueous extract of Cassia occidentalis against the chromosomal aberrations (CA) produced in vivo by benzo[a]pyrene (B[a]P) and cyclophosphamide (CP) in mice. Animals (male mice) were treated with three doses of plant extract (50 mg/kg, 250 mg/kg and 500 mg/kg) for 7 days prior to the administration of single dose of mutagens (B[a]P 125 mg/kg oral; CP 40 mg/kg i.p.). The results indicated that C. occidentalis was not genotoxic per se and exerted no other toxic signs and symptoms in treated animals. The chromosomal aberrations produced by B[a]P and CP were significantly reduced (p < 0.001) by C. occidentalis pre-treatment. Furthermore, animals treated with plant extract showed a reduced level of cytochrome P 450 (Cyt P 450) and elevated levels of glutathione S-transferase (GST) activity and glutathione content in the liver. It seems that C. occidentalis exerts its antimutagenic activity by modulating the xenobiotic activation and detoxification mechanisms.     

Demonstration of Benzo(a)pyrene-Induced DNA Damage in Mice by Alkaline Single Cell Gel Electrophoresis: Evidence for Strand Breaks in Liver but Not in Lymphocytes and Bone Marrow

Abstract: Alkaline single cell gel electrophoresis (also known as the‘comet assay') was used to measure DNA strand breaks and alkali-labile sites in peripheral lymphocytes, bone marrow and liver cells of C57BL/6 mice orally exposed to benzo(a)pyrene. Although this polycyclic aromatic hydrocarbon is a well-known genotoxic agent, little is known about to what extent it actually induces DNA strand breaks in peripheral lymphocytes and other tissues after in vivo exposure. Significant and dose-related damage was observed in liver cells after three days of exposure (lowest observed effect level being 3×100 mg benzo(a)pyrene/kg b.wt.). No such damage could be observed in the lymphocytes and bone marrow cells even after administration of 3×150 mg benzo(a)pyrene/kg b.wt. The reference substance cyclophosphamide produced pronounced DNA damage in lymphocytes and bone marrow cells already in a single dose of 100 mg/kg b.wt. The present mouse study questions the usability of DNA strand breaks in peripheral lymphocytes as an indicator of benzo(a)pyrene-induced genotoxicity.     

Modulatory effects of gentisic acid against genotoxicity and hepatotoxicity induced by cyclophosphamide in Swiss albino mice

Objectives This study evaluated the protective effects of gentisic acid (GA) against genotoxicity and hepatotoxicity induced by cyclophosphamide (CP) in Swiss albino mice. Methods Mice were pretreated with GA orally at doses of 50 and 100 mg/kg for 14 consecutive days before the administration of a single intraperitoneal dose of 50 mg/kg CP. The ameliorative effect of GA on genotoxicity was studied using the in‐vivo bone marrow micronuclei induction test, DNA integrity and alkaline unwinding assay. The activity of various oxidative stress enzymes were estimated in hepatic tissue. Key findings A single intraperitoneal administration of CP in mice increased the malondialdehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione reductase, catalase and quinone reductase), and induced DNA strand breaks and micronuclei induction. Oral pretreatment with GA at both doses caused a significant reduction in malondialdehyde and glutathione levels, restoration of antioxidant enzyme activity, reduction in micronuclei formation and DNA fragmentation. Serum toxicity marker enzymes such as aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were increased after CP treatment but restored in GA pretreated groups. Conclusion The results support the protective effect of GA against CP induced genotoxicity and hepatotoxicity.     

Synergistic effects of piperine and curcumin in modulating benzo(a)pyrene induced redox imbalance in mice lungs

The objective of the present study was to evaluate the effects of curcumin alone and with adjuvant piperine against benzo(a)pyrene (BaP) induced oxidative stress in lungs of male Swiss albino mice. Mice were pretreated either with curcumin (100 mg/kg body weight), or piperine (20 mg/kg body weight), and in combination of both for one week, followed by single dose of benzo(a)pyrene (125 mg/kg body weight) treatment. Treatment with benzo(a)pyrene resulted in increased levels of lipid peroxides (LPO), protein carbonyl content (PCC) and with consequent decrease in the levels of tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and reduced glutathione (GSH), which however, were increased significantly following curcumin treatment, but the increase was more pronounced when piperine was used as an adjuvant. BaP treatment alone did not alter significantly the GST activity. Pretreatment with curcumin increased the GST activity in BaP treated group, which was enhanced further upon synergistic treatment with piperine and curcumin. Therefore, combined administration of curcumin and piperine shall prove to be more effective in attenuating BaP induced toxicity.     

Chemoprotective effect of the tetrahydrofuran lignan grandisin in the in-vivo rodent micronucleus assay

Objectives The chemoprotective effect of the tetrahydrofuran lignan grandisin against DNA damage induced by cyclophosphamide (200 mg/kg) has been evaluated using the in vitro rodent micronucleus assay. Methods The effects of a daily oral administration of grandisin (2, 4, or 8 mg/kg) for five days before exposure to cyclophosphamide on the frequency of micronucleus in the bone marrow of normal mice exposed and unexposed to cyclophosphamide were investigated (n = 5 per group). Electrochemical measurements were applied to investigate whether the antimutagenic effects of grandisin could be, at least in part, a consequence of its or its metabolite's antioxidant properties. Key findings Grandisin did not show mutagenic effects on the bone marrow cells of exposed mice. On the other hand, the oral administration of grandisin (2, 4, or 8 mg/kg) per day reduced dose‐dependently the frequency of micronucleus, induced by cyclophosphamide, in all groups studied. Cyclic voltammograms showed two peaks for a grandisin metabolite, which were absent for grandisin. Conclusions Under the conditions tested herein, this study has shown that mice treated with grandisin presented, in a dose‐dependent manner, a protective effect against cyclophosphamide‐induced mutagenicity. This effect could be, at least in part, associated to grandisin bioactivation. These data open new perspectives for further investigation into the toxicology and applied pharmacology of grandisin.     

Protective effects of baicalein and wogonin against benzo[a]pyrene- and aflatoxin B(1)-induced genotoxicities.

To evaluate the protective effects of baicalein and wogonin against benzo[a]pyrene- and aflatoxin (AF) B(1)-induced toxicities, the effects of these flavonoids on the genotoxicities and oxidation of benzo[a]pyrene and AFB(1) were studied in C57BL/6J mice. Baicalein and wogonin reduced benzo[a]pyrene and AFB(1) genotoxicities as monitored by the umuC gene expression response in Salmonella typhimurium TA1535/pSK1002. Baicalein added in vitro decreased liver microsomal benzo[a]pyrene hydroxylation (AHH) activity with an ic(50) of 33.9 +/- 1.4 microM at 100 microM benzo[a]pyrene. Baicalein also inhibited AFQ(1) and AFB(1)-epoxide formation from AFB(1) (50 microM) oxidation (AFO) with ic(50) values of 22.8 +/- 1.4 and 5.3 +/- 0.8 microM, respectively. However, the in vitro inhibitory effects of wogonin on AHH and AFO activities in liver microsomes were less than those of baicalein as inhibition by 500 microM wogonin was only about 51-65%. Treatment of mice with liquid diets containing 5 mM baicalein and wogonin resulted in 22 and 49% decreases in hepatic AHH activities, respectively. Baicalein treatment resulted in 39 and 32% decreases in AFQ(1) and AFB(1)-epoxide formation from liver microsomal AFO, respectively. Wogonin treatment resulted in 39 and 47% decreases in AFQ(1) and AFB(1)-epoxide formation, respectively. A 1-week pretreatment with wogonin significantly decreased hepatic DNA adduct formation in mice treated with 200 mg/kg of benzo[a]pyrene via gastrogavage. These in vitro and in vivo effects suggested that baicalein and wogonin might have beneficial effects against benzo[a]pyrene- and AFB(1)-induced hepatic toxicities and that wogonin had a stronger protective effect in vivo.     

The influence of verapamil on the clastogenic effect of cyclophosphane in somatic cells from BALB/c and C57Bl/6 mice]

The method of chromosome aberration count in the bone marrow cells of male BALB/c and C57Bl/6 mice was used to study the influence of intraperitoneal injection of verapamil in doses of 0.1-10 mg/kg and its administration into the stomach in doses of 2.5-10 mg/kg on the clastogenic effect of cyclophosphamide (10 mg/kg intraperitoneally) in a single and repeated (5 times at intervals of 24 h) administration. In repeated administration in all the doses used, verapamil significantly intensified the mutagenic activity of cyclophosphamide in C57Bl/6 mice and in doses 10 mg/kg in BALB/c mice. A single intraperitoneal verapamil injection (0.1-0.4 mg/kg) caused a statistically increase in the clastogenic effect of cyclophosphan in mice of both strains. The same effect was encountered in intraperitoneal injection (2.5 mg/kg) and administration into the stomach (5 mg/kg) of the calcium antagonist in BALB/c mice. Thus, the effect of verapamil on cyclophosphamide clastogenic activity depends on the dose, method, and schedule of administration of the calcium antagonist.     

Anticonvulsant actions of DS 103-282. Pharmacological studies in rodents and the baboon, Papio papio

The anticonvulsant actions of DS 103-282 [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3- benzothiadazole , tizanidine], have been evaluated after intraperitoneal administration in DBA/2 mice (seizures induced by sound), in Swiss S mice (seizures induced by N-methyl-D,L-aspartate; NMDLA ) and following intravenous or oral administration in Papio papio (seizure responses to intermittent photic stimulation). Protection against sound-induced seizures occurred after intraperitoneal administration of DS 103-282 (0.66-3.33 mg/kg). The ED50 doses for suppression of the tonic, clonic and wild-running phases of sound-induced seizures were 0.53, 0.79 and 1.3 mg/kg respectively. This protective effect of DS 103-282 (1.5 mg/kg, i.p.) was maximal after 30 min and was maintained for 60-120 min. Seizures induced by NMDLA were not suppressed by DS 103-282 (3.3-10 mg/kg, i.p.). In the baboons, a transient protection against photomyoclonic responses was observed 1 hr after intravenous administration of DS 103-282 (2-4 mg/kg). A similar profile of action was seen after oral administration of larger doses of DS 103-282 (16-32 mg/kg). Unwanted effects of DS 103-282 included transient piloerection, slight disturbance of gait and a fall in rectal temperature in mice, and muscular hypotonia and signs of sedation in baboons. These studies demonstrate an anticonvulsant action of DS 103-282, in both rodent and primate models of epilepsy, but do not support a postsynaptic blockade in excitatory neurotransmission as the mechanism of this action.     

前胡甲素对小鼠局灶性脑缺血的保护作用

目的观察前胡甲素(Pd-Ia)对小鼠局灶性脑缺血损伤的保护作用及特点。方法线栓法制备小鼠大脑中动脉栓塞脑缺血损伤模型。Pd-Ia(1,5,10mg/kg)在缺血前0.5h腹腔给药1次;或在缺血前1,0.5h、缺血同时、再灌注同时、再灌后0.5h及再灌后1h各腹腔给予Pd-Ia5mg/kg。脑缺血1.5h,再灌注24h后,测定小鼠神经功能缺失评分、脑梗死体积、脑水肿等评定脑缺血损伤的指标;测定血清中丙二醛(MDA)和超氧化物岐化酶(SOD)的活性。结果Pd-Ia(5,10mg/kg)缺血前0.5h给药及Pd-Ia5mg/kg缺血前0.5h、缺血同时、再灌注同时及再灌后0.5h给药可明显改善小鼠神经功能损伤,减小脑梗死体积和减轻脑水肿程度,且以再灌注同时单次给药效果最为显著;Pd-Ia(5,10mg/kg)能够明显提高脑缺血损伤小鼠血清中SOD活性,降低MDA含量。结论Pd-Ia保护小鼠局灶性脑缺血急性损伤,最佳剂量为5mg/kg,最佳治疗时间点为再灌注同时;其保护脑缺血损伤的机制可能与抑制脂质过氧化、提高氧化酶的活性有关。     

Synergistic effects of piperine and curcumin in modulating benzo(a)pyrene induced redox imbalance in mice lungs

The objective of the present study was to evaluate the effects of curcumin alone and with adjuvant piperine against benzo(a)pyrene (BaP) induced oxidative stress in lungs of male Swiss albino mice. Mice were pretreated either with curcumin (100?mg/kg body weight), or piperine (20?mg/kg body weight), and in combination of both for one week, followed by single dose of benzo(a)pyrene (125?mg/kg body weight) treatment. Treatment with benzo(a)pyrene resulted in increased levels of lipid peroxides (LPO), protein carbonyl content (PCC) and with consequent decrease in the levels of tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and reduced glutathione (GSH), which however, were increased significantly following curcumin treatment, but the increase was more pronounced when piperine was used as an adjuvant. BaP treatment alone did not alter significantly the GST activity. Pretreatment with curcumin increased the GST activity in BaP treated group, which was enhanced further upon synergistic treatment with piperine and curcumin. Therefore, combined administration of curcumin and piperine shall prove to be more effective in attenuating BaP induced toxicity.     

Seizure promotion and protection by D-1 and D-2 dopaminergic drugs in the mouse

Mice injected with pilocarpine (100-400 mg/kg plus 1 mg/kg methylscopolamine), picrotoxin (0.75-6 mg/kg) or strychnine (0.75-6 mg/kg) exhibited clonic or clonic/tonic convulsions. Pretreatment with the D-1 agonist CY 208-243 (0.375-1.5 mg/kg) dose-dependently potentiated the convulsions elicited by 100 mg/kg pilocarpine, but had neither a convulsant nor anticonvulsant effect in mice receiving picrotoxin (3 or 6 mg/kg) or strychnine (0.75 or 1.5 mg/kg). This facilitatory effect of CY 208-243 was abolished by the D-1 antagonist SCH 23390 (0.2 mg/kg). SCH 23390 by itself (0.05-0.8 mg/kg) dose-dependently protected mice against pilocarpine (400 mg/kg) seizures. Stimulating D-2 receptors with LY 171555 (0.167-4.5 mg/kg) dose-dependently protected mice against seizure activity induced by pilocarpine, but neither protected nor sensitised mice given picrotoxin or strychnine. The neuroleptics haloperidol (1-4 mg/kg), sulpiride (10-50 mg/kg), metoclopramide (1.25-6.25 mg/kg), thioridazine (0.5-2 mg/kg) and clozapine (0.5-2 mg/kg) had no effect on the seizure threshold to 100 mg/kg pilocarpine by themselves, although 10 mg/kg thioridazine and clozapine caused 100% convulsions, possibly through a toxic action. When administered in conjunction with a minimally effective quantity of CY 208-243 (0.375 mg/kg), however, all five neuroleptics interacted synergistically with the D-1 agonist to promote convulsions to pilocarpine (100 mg/kg). No such interaction occurred between submaximally protective doses of the D-1 blocker SCH 23390 (0.05 and 0.2 mg/kg) and a wide range of doses of the D-2 stimulant LY 171555 (0.167-4.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-genotoxicity and glutathione S-transferase activity in mice pretreated with caffeinated and decaffeinated coffee.

In vivo anti-genotoxic effects of caffeinated and decaffeinated instant coffee were compared in mice after pretreatment either by gavage for 10 consecutive days or in the drinking water for 2 weeks. Changes in hepatic sulfhydryl (-SH) content and glutathione S-transferase (GST) activity were evaluated in pretreated animals. Both caffeinated and decaffeinated instant coffee induced a moderate increase in -SH content and GST activity following pretreatment (with 70, 140 and 280 mg/kg body weight) by gavage for 10 days. This enhancement was not always dose dependent. The maximum effect on GST activity was observed at a dose of 140 mg/kg body weight/day. However, such an effect was not observed after administration of drinking water containing 2% caffeinated/decaffeinated instant coffee for 2 weeks. Results of the bone marrow micronucleus test for evaluating genotoxic effects revealed that both caffeinated and decaffeinated instant coffee (140 mg/kg body weight/day) could exert significant anti-genotoxic effects against ip injected benzo[a]pyrene (BP), cyclophosphamide (CPH), 7,12-dimethylbenz[a]anthracene (DMBA), mitomycin C (MMC) and procarbazine (PCB) in animals pretreated by gavage. Anti-genotoxic effects against BP, DMBA and urethane (URE) were evaluated in animals that received drinking water containing 2% caffeinated/decaffeinated instant coffee for 2 weeks. With the exception of the anti-genotoxic effect of decaffeinated coffee against DMBA, there was no significant change in genotoxicity after the above pretreatment. From this work, there is no evidence for any significant difference in the in vivo anti-genotoxicity of caffeinated and decaffeinated instant coffee.     

Differential sensitivity of Ah-responsive mice to beta-naphthoflavone-induced metabolism and mutagenesis of benzo[a]pyrene and aflatoxin B1

Effects of the administration to C57BL/6ha (Ah-responsive) mice of a low (10 mg/kg) and a high dose (150 mg/kg) of beta-naphthoflavone (BNF) on the hepatic microsome-mediated mutagenesis and metabolism of benzo[a]pyrene (BP) and aflatoxin B1 (AFB1) were studied. Hepatic microsome-mediated mutagenesis of benzo[a]pyrene was not enhanced by the low dose (10 mg/kg) but at the high dose (150 mg/kg) the mutagenic activation was enhanced several fold relative to control (corn oil-treated). Mutagenic activity of aflatoxin B1 was however depressed by both the low and the high doses of beta NF. These results are consistent with the effects of beta NF administration on hepatic microsome-mediated metabolism of BP to its phenolic products and on the metabolism of aflatoxin B1 to aflatoxin M1 catalyzed by aflatoxin B1-4-hydroxylase. Relative to control, pretreatment of the mice with 10 mg/kg beta NF did not induce aryl hydrocarbon hydroxylase activity (a measure of BP metabolism), however, the same pretreatment induced the metabolism of AFB1 to AFM1 by 2.7 to 4.7-fold. Microsomal preparations from 150 mg/kg beta NF-pretreated mice showed a 3-fold induction of aryl hydrocarbon hydroxylase activity and a 6.8-fold induction of AFB1-4-hydroxylase activity. These results suggest that two different enzyme systems are involved in the metabolism of BP and the metabolism of AFB1 to AFM1.     

Cysteine isopropylester protects against paracetamol-induced toxicity.

Cysteine isopropylester (CIPE), a novel ester of cysteine, has been synthesized in order to evaluate its potential as a chemoprotectant. The increased lipophilicity of the ester relative to cysteine should facilitate its entry into cells where, following hydrolysis, it should act as an intracellular source of cysteine or be utilized for the synthesis of glutathione so protecting the cell against various types of chemical insult. In this study, we evaluate the ability of CIPE to protect against paracetamol-induced hepatotoxicity in mice. When administered to mice, CIPE produced a rapid but transient elevation of levels of non-protein sulphydryls (NPSH) in liver, lung, kidney and spleen. The greatest increase in NPSH was seen in the lung, but after 60 min all NPSH values had returned to control levels, demonstrating the capacity of the mouse to rapidly metabolize both CIPE and cysteine. In mice pretreated with benzo(a)pyrene, CIPE protected against paracetamol-induced toxicity as measured by the prevention of mortality, the fall in hepatic NPSH and the decreased elevation of serum transaminases. CIPE (1.5 mmol/kg) appeared as effective as N-acetylcysteine (1.5 mmol/kg). Higher doses of CIPE (3.0 mmol/kg) alone were toxic to mice induced with benzo(a)pyrene but not to control or phenobarbitone-induced mice. The mechanism of this increased toxicity is unclear. CIPE has a short in vivo half life but was capable of protecting against paracetamol-induced toxicity. The potential of CIPE and other related cysteine esters to act as chemoprotectants merits further investigation.     

Inhibition by plant phenols of benzo[a]pyrene-induced nuclear aberrations in mammalian intestinal cells: a rapid in vivo assessment method

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.     

Citrus extract modulates genotoxicity induced by cyclophosphamide in mice bone marrow cells

The protective effect of citrus extract was investigated by using the micronucleus assay for anticlastogenic activity in mouse bone marrow cells; liver glutathione (GSH) content was determined against toxicity induced by cyclophosphamide. Mice were orally (gavage) pretreated with solutions of citrus peel extract (Citrus aurantium var. amara) prepared at three different doses (100, 200 and 400 mg kg(-1;) body weight) for 7 consecutive days. Then mice were injected intraperitoneally on the seventh day with cyclophosphamide (50 mg kg(-1)) and after 24 h killed for the evaluation of micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow cells. Non-protein thiol levels in liver were estimated in mice injected with citrus extract with or without cyclophosphamide treatment. Administration of citrus extract before cyclophosphamide treatment significantly reduced the frequency of MnPCEs in mice bone marrow compared with the group treated with cyclophosphamide alone (P<0.0001-0.05). Citrus extract at a dose of 400 mg kg(-1) reduced MnPCEs 2.8 fold against genotoxicity induced by cyclophosphamide. Administration of cyclophosphamide depleted the GSH level in liver. Citrus extract showed excellent scavenging effects on 1,1-diphenyl-2-picryl hydrazyl radical (DPPH) at a concentration of 1.6 mg mL(-1). Application of citrus extract 1 h before cyclophosphamide treatment allowed GSH content to reach the normal level. It appeared that citrus extract, particularly flavonoids constituents with antioxidative activity, may return the GSH level to normal in stress conditions and reduces genotoxicity induced by cyclophosphamide in bone marrow cells.     

Protective Effect of Cassia Occidentals Extract on Chemical-Induced Chromosomal Aberrations in Mice

ABSTRACT

This study was conducted to determine the antimutagenic potential of aqueous extract of Cassia occidentalis against the chromosomal aberrations (CA) produced in vivo by benzo[a] pyrene (B[a]P) and cyclophosphamide (CP) in mice. Animals (male mice) were treated with three doses of plant extract (50mg/kg, 250mg/kg and 500mgAg) for 7 days prior to the administration of single dose of mutagens (B[a]P 125mg/kg oral; CP 40mg/kg i.p). The results indicated that C. occidentalis was not genotoxic per se and exerted no other toxic signs and symptoms in treated animals. The chromosomal aberrations produced by B[a]P and CP were significantly reduced (p < 0.001) by C. occidentalis pre-treatment. Furthermore, animals treated with plant extract showed a reduced level of cytochrome P 450 (Cyt P 450) and elevated levels of glutathione S-transferase (GST) activity and glutathione content in the liver. It seems that C. occidentalis exerts its antimutagenic activity by modulating the xenobiotic activation and detoxification mechanisms.     

Effects of aflatoxin B1 on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo(a)pyrene treatment in chickens.

Administration of 1.5 mg aflatoxin B1 (AFB1)/kg in DMSO as a single i.p. dose to 80 mg phenobarbital/kg i.p. for 3 d pretreated chickens showed significant decrease in the levels of electron transport components and drug metabolizing enzymes compared to phenobarbital administration alone. Induction of mixed function oxidase enzymes due to phenobarbital was not affected by the AFB1 pretreatment. AFB1 administration to 20 mg benzo(a)pyrene/kg in safflower seed oil i.p. for 2 d pretreated chickens showed significant decrease in cytochrome b5 and drug metabolizing enzymes when compared with benzo(a)pyrene treatment alone. However, cytochrome P450 level was slightly higher due to administration of AFB1 to benzo(a)pyrene-injected chickens. The results indicate that the phenobarbital-induced cytochrome P450 is more susceptible to AFB1 than benzo(a)pyrene-induced cytochrome P450.     

Antagonism of caffeine-induced convulsions by ethanol and dizocilpine (MK-801) in mice

Ethanol (1 and 2 g/kg, i.p.) and MK-801 (1 mg/kg, i.p.), N-methyl-D-aspartate (NMDA) receptor antagonist, offered protection against caffeine-induced convulsions in mice. Subeffective doses of ethanol (0.5-g/kg, i.p.) and MK-801 (0.5 mg/kg, i.p.) when administered concurrently, did not provide a facilitatory anticonvulsant action against caffeine-induced convulsions. Ethanol (0.5 g/kg, i.p.) when administered concurrently with adenosine (100 mg/kg, i.p.) or dipyridamole (5 mg/kg, i.p.) elicited a facilitatory anticonvulsant action. However, concurrent administration of subeffective doses of MK-801 (0.5 mg/kg i.p.) with adenosine (100 mg/kg, i.p.) did not offer a facilitatory anticonvulsant action against caffeine-induced convulsions. The protective effect of ethanol (1 g/kg, i.p.) against caffeine-induced convulsions was reversed by an imidazobenzodiazepine, Ro 15-4513 (4 mg/kg, i.p.). Ro 15-4513 did not produce any proconvulsant effect with caffeine. It is suggested that ethanol and MK-801 elicit their anticonvulsant actions against caffeine-induced convulsions through different receptor mechanisms and that the anticonvulsant action of ethanol may be partly attributed to its ability to act via central adenosinergic mechanisms.