Potentiation of mercury-induced nephrotoxicity by endotoxin in the Sprague-Dawley rat

Endotoxin (lipopolysaccharide; LPS) and mercury are nephrotoxic compounds of food safety concern. Endotoxin is a product of cell walls of gram negative bacteria. Humans are constantly exposed to LPS through food, water and air. Food is the main source of mercury exposure for humans. Endotoxin potentiates the toxicity of a number of xenobiotics, but its interaction with nephrotoxic heavy metals has not been investigated. We tested the hypothesis that endotoxin enhances mercury-induced nephrotoxicity. Thirty-two, 41-43-day-old, male Sprague-Dawley rats were allocated randomly to four groups of eight rats each as follows: group I received 0.9% sodium chloride, group II received 2.0 mg of Escherichia coli 0128:B12 LPS kg(-1) once, group III received 0.5 mg mercuric chloride kg(-1) once, and group IV received 2.0 mg E. Coli 0128:B12 LPS kg(-1) once 4 h before receiving 0.5 mg mercury chloride kg(-1) once. Mercury, LPS and 0.9% sodium chloride were all injected IV through the tail vein. Rats were monitored for 48 h after mercury injection. Serum creatinine, urea nitrogen, and polyuria were significantly increased in rats given LPS plus mercury relative to those given either agent alone or saline (P相似文献   

Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines

Zalypsis^® is a new synthetic alkaloid tetrahydroisoquinoline antibiotic that has a reactive carbinolamine group. This functionality can lead to the formation of a covalent bond with the amino group of selected guanines in the DNA double helix, both in the absence and in the presence of methylated cytosines. The resulting complex is additionally stabilized by the establishment of one or more hydrogen bonds with adjacent nucleotides in the opposite strand as well as by van der Waals interactions within the minor groove. Fluorescence-based thermal denaturation experiments demonstrated that the most favorable DNA triplets for covalent adduct formation are AGG, GGC, AGC, CGG and TGG, and these preferences could be rationalized on the basis of molecular modeling results. Zalypsis^®-DNA adducts eventually give rise to double-strand breaks, triggering S-phase accumulation and apoptotic cell death. The potent cytotoxic activity of Zalypsis^® was ascertained in a 24 cell line panel. The mean IC₅₀ value was 7 nM and leukemia and stomach tumor cell lines were amongst the most sensitive. Zalypsis^® administration in four murine xenograft models of human cancer demonstrates significant tumor growth inhibition that is highest in the Hs746t gastric cancer cell line with no weight loss of treated animals. Taken together, these results indicate that the potent antitumor activity of Zalypsis^® supports its current development in the clinic as an anticancer agent.     

Potentiation of lidocaine toxicity by pentobarbital in the dog

In order to evaluate the usefulness of pentobarbital in the treatment of lidocaine-induced convulsions, 12 dogs received an intravenous infusion of 2 mg/kg/min lidocaine until the onset of convulsions. One minute after the onset of convulsions 6 of 12 dogs received 30 mg/kg pentobarbital administered iv over 1 min, and the remaining 6 dogs were injected with an equal volume of 0.9% NaCl. Following pentobarbital, 5 of 6 dogs died within minutes after the injection, while 5 of 6 dogs that received the saline solution survived. In order to test the hypothesis that the death of the animals was due to respiratory depression, a third group of 6 dogs was given similar doses of lidocaine and pentobarbital. At the same time that the barbiturate was given, artificial ventilation was initiated. Four out of six dogs survived, but the other two died of cardiovascular collapse, with the electrocardiogram and arterial blood gas concentrations remaining within normal limits until death. It is concluded that pentobarbital should not be administered in the treatment of lidocaine-induced convulsions. Assisted ventilation does not offer complete protection in the presence of this interaction.     

Implications of cytochrome P450 genetic polymorphisms on the toxicity of antitumor agents

In the treatment of cancer, a narrow therapeutic window generally exists between toxicity and suboptimal therapy. In addition, interindividual variation in drug metabolism seriously complicates therapy. Genetic polymorphisms in phase 1 and phase 2 enzymes are present in the population and may explain part of the observed interindividual variation in drug pharmacokinetics. For the cytochrome P450 superfamily, information on variant alleles encoding enzymes with decreased activity is rapidly on the increase. The potential of applying pharmacogenetic screening before therapy in the treatment of cancer seems to be greatest for CYP2B6 (cyclophosphamide treatment), CYP2C8 (paclitaxel therapy), and CYP3A5; however, the drugs of interest still need to be identified for this latter enzyme.     

Mutagenicity of commercial hair dyes in Salmonella typhimurium TA98

Commercial permanent hair-dye formulations containing p-phenylenediamine, resorcinol and aminophenols were incubated with hydrogen peroxide and then tested for their ability to induce reverse mutations in Salmonella typhimurium TA98. Approximately half of the formulations (12 out of 25) gave positive results. The activity varied widely in degree and was observed only in the presence of an S-9 microsomal fraction from Aroclor-induced male rats. Five of the 12 positive formulations and one negative dye were administered topically to male rats; with one exception the urines of animals treated with the mutagenic hair dyes gave positive results in the presence of the S-9 mix.     

Potentiation of tricyclic antidepressant toxicity by physostigmine in mice

Subtoxic doses of physostigmine have been found to potentiate the convulsive toxicity and lethality of amitriptyline and imipramine in CD1 and B6A mice. Neostigmine failed to potentiate the toxicity and lethality of imipramine. Physostigmine tended to protect mice against atropine-induced lethality. These data suggest the site of toxicity of this drug-drug interaction between the tricyclic antidepressants and physostigmine may be occurring in the CNS through a mechanism distinct from the anticholinergic actions of the antidepressants.     

Mutagenicity testing of 2,3,7,8-tetrachlorodibenzo-p-dioxin in histidine auxotrophs of Salmonella typhimurium

The mutagenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been examined using the Salmonella typhimurium histidine auxotrophs TA1535, TA100, TA1538, TA98, and TA1537. TCDD did not show mutagenicity in any of these auxotrophs in the presence of mammalian metabolic activating systems isolated from the livers of Arochlor 1254-treated rats, Arochlor 1254-treated hamsters, or TCDD-treated hamsters. Test run in the absence of NADP⁺-dependent metabolic activation failed to reveal any mutagenic activity of TCDD.     

Potentiation of gastric toxicity of ibuprofen by paracetamol in the rat.

A fixed dose combination of ibuprofen (400 mg) and paracetamol (325 mg) is by far the most extensively prescribed medicament for a variety of musculoskeletal disorders in India. Following clinical observations that this drug combination induces significant adverse effects, its gastric toxicity was investigated in rats. Ibuprofen (25 mg kg-1 p.o., twice daily x 5 days), paracetamol (20 mg kg-1 p.o, twice daily x 5 days), and a combination of the two, had no significant effect on free and total gastric acidity in pylorus-ligated rats. Ibuprofen induced visible gastric ulceration whereas paracetamol did not. However, the combination of these two drugs had an additive effect inducing severe gastric erosions, ulcerations and bleeding. The augmented toxicity of this drug combination appeared to be a consequence of attenuated gastric mucin activity and reduction in the gastric muco-protective barrier. This investigation indicates the likely hazard of an irrational fixed dose drug combination.     

Effects of verapamil on the cellular accumulations and toxicity of several antitumor drugs in 9-hydroxy-ellipticine-resistant cells

9-OH-Ellipticine (9-OH-E)-resistant cells are not only resistant to the DNA topoisomerase II inhibitors, but also to some other antitumor agents, such as actinomycin D (AD), adriamycin (ADM), daunorubicin and vincristine. It was previously shown that a decreased uptake accounts for the cross-resistance of these cells to AD and ADM which then suggested that the 9-OH-E-resistant cells might display some of the properties usually associated with the multidrug resistance phenotype. In this work, we have examined the effects of verapamil, a drug which is known to overcome the multidrug resistance, on the toxicity and the cellular accumulation of four cytotoxic agents: 9-OH-E, 2N-methyl-9-hydroxy-ellipticinium (NMHE), AD and ADM, either on 9-OH-E resistant cells or on a multidrug resistant subline derived from the same sensitive parental cells. Verapamil inhibited the cellular accumulation of the ellipticine derivatives in the sensitive DC-3F cells, and the toxicity of these drugs on these cells was correspondingly decreased. On either one of the resistant cell lines, verapamil had no effect on the toxicity and the cellular accumulation of 9-OH-E. In contrast, in the presence of verapamil, the cellular accumulation of NMHE by the 9-OH-E and the multidrug resistant cells was about 50% and 300% increased, respectively. The increased NMHE cellular concentration in the multidrug resistant cells was associated with an 8-fold increased toxicity. The major structural characteristics which might account for this difference between the sensitivities of both ellipticine derivatives to the effects of verapamil on the multidrug resistant cells is the presence of a positive charge on the nitrogen in position 2 of the 6H-pyridocarbazole molecule. Finally, verapamil circumvented partially the cross-resistance of DC-3F/9-OH-E cells to AD and ADM by increasing the accumulation of these drugs inside the cells.     

Acute toxicity studies of aluminium compounds: antidotal efficacy of several chelating agents

Four aluminum compounds--nitrate, chloride, sulphate and bromide--were administered orally and intraperitoneally to rats and mice. The LD50-values (14 days) were determined. The majority of deaths occurring during the first four days. The clinical and physical signs appearing after intoxication include among other lethargy, decreased locomotor activity, piloerection, weight loss and perorbital bleeding. After 14 days no alterations in liver and renal functions were detected in the animals which received intraperitoneally the LD50-values of aluminum nitrate as a single dose. Aluminum concentrations were highest in liver and spleen. No histopathological lesions could be observed. To compare the efficacies of nine chelating agents on the toxicity of aluminum in mice, the therapeutic index and the therapeutic effectiveness of each chelating agent have been calculated. Malic, succinic, oxalic and malonic acids showed the best results with malic and succinic acids being the most effective. Deferoxamine mesylate (DFOA), sodium salicylate, L-cysteine and citric acid were not so effective as antidotes for acute aluminum toxicity. Aurin tricarboxylic acid (ATCA) should not be used due to its high toxicity.     

Potentiation of the toxicity of basic peptides from rattlesnake venoms by sodium acetate

The potentiating effect of sodium acetate on the toxicity of crotamine from Crotalus durissus terrificus venom, E toxin from Crotalus horridus horridus venom, and myotoxin a from Crotalus viridus viridis venom was examined. Subcutaneous injection of 6.3 mg/kg body weight of either crotamine or E toxin in 0.6 ml of water or myotoxin a in 0.6 ml of 0.05 M Tris/0.1 M NaCl buffer, pH 9.0, failed to produce lethality in mice. Injection of either E toxin or crotamine at doses of 4.0 mg/kg in 0.6 ml of 20 mM phosphate, pH 7.2, containing 1 M sodium chloride also failed to produce lethality. However, when any of the toxins were injected in 0.4 ml of 1 M sodium acetate, pH 7.0, lethality was observed. LD50 values of 1.43 mg/kg for E toxin, 1.39 mg/kg for crotamine and 0.56 mg/kg for myotoxin a were determined under these conditions. Lethality was also observed when either sodium propionate or sodium butyrate was used as a carrier for E toxin. The effect of these two buffers on crotamine and myotoxin a was not examined. Injection of E toxin s.c. in water followed at various time intervals with i.p. injections of 1 M sodium acetate produced lethality, even when the acetate was injected up to 4 hr after the toxin challenge.     

Mutagenicity of a halocarbon refrigerant monochloro-difluoromethane (R-22) in Salmonella typhimurium

Commercially available refrigerant R-22 was found to produce a reproducable positive response in the Salmonella reverse mutation assay (Ames' test) modified for testing gases. The positive response was shown to be dependent neither on the presence of rat post-mitochondrial supernatant in the incubation medium nor on the presence of known mutagenic gases contaminating the commercial grade refrigerant.     

Potentiation of ethanol toxicity by cyanamide in relation to acetaldehyde accumulation

The possibility that acetaldehyde accumulation potentiates the acute toxicity of ethanol was studied by pretreating rats with cyanamide, an aldehyde dehydrogenase inhibitor. At 30 min after administration of ethanol (7 to 9 g/kg, po), the levels of acetaldehyde in femoral venous blood of cyanamide-treated rats were increased from 10 to 20 to 600 mumol/liter and at death the concentrations of acetaldehyde in heart blood and cerebrospinal fluid were still 7 to 9 and 4 to 9 times higher, respectively, than in rats given ethanol only. The cyanamide pretreatment (25 mg/kg) significantly increased the mortality of rats given 6.5 to 7.0 g/kg ethanol and decreased the LD50 of ethanol from 7.3 to 5.9 g/kg. Cyanamide increased the late mortality, possibly because of sustained acetaldehyde accumulation. Although administration of the alcohol dehydrogenase inhibitor, 4-methylpyrazole (4-MP, 10 mg/kg), prevented the accumulation of acetaldehyde, it only partly counteracted the effect of cyanamide on mortality. After coadministration of cyanamide and 4-MP, the LD50 of ethanol was 6.5 g/kg, and after 4-MP alone, 6.7 g/kg. 4-MP by itself seemed to increase the early mortality of rats to ethanol poisoning. The results suggest that the potentiating effect of cyanamide on ethanol toxicity can partly be explained by acetaldehyde accumulation and that 4-MP can be used to inhibit this accumulation providing its central depressant effect is taken into account.     

Protection by Mikania laevigata (guaco) extract against the toxicity of Philodryas olfersii snake venom

Philodryas olfersii is responsible for most colubrid snakebites in Brazil. In this work, we examined the ability of an ethanolic extract from Mikania laevigata (guaco) leaves to protect against the in vitro neuromuscular activity of P. olfersii venom in mouse phrenic nerve-diaphragm (PND) and chick biventer cervicis (BC) preparations. M. laevigata extract caused moderate twitch-tension facilitation at low concentrations (107.4 ± 6.2% with 20 μl/ml and 118.9 ± 9.3% with 40 μl/ml in PND, and 120.7 ± 7.7% with 40 μl/ml and 114.5 ± 4.4% with 50 μl/ml in BC after 120 min; n = 4-6, mean ± SEM). In PND, the ethanol alone (40 μl/ml, n = 4) did not change the twitch-tension when compared with control. However, in BC, the ethanol produced a higher facilitation when compared to control. At higher concentrations (>50 μl/ml) the extract caused total and reversible blockade in both preparations. Venom (50 μg/ml) caused partial blockade in PND (58.5 ± 12%, n = 4) and almost total blockade in BC (93.5 ± 2.2%, n = 4). Pretreatment of the preparations with extract (40 μl/ml) for 30 min before incubation with venom (50 μg/ml) completely protected PND from neuromuscular blockade and delayed the blockade in BC. The extract alone caused only mild morphological alterations (12.5 ± 0.5% and 10.9 ± 2.3% fiber damage in PND and BC, respectively, compared to 2.3 ± 0.3% and 3 ± 0 in controls; n = 3), with no increase in expression of the inflammatory cytokines TNFα and IFNγ. The ethanol alone also caused slight muscle damage: 4.3 ± 2.4% in PND and 6.7 ± 3.3% in BC (both n = 3) and little or no TNFα and IFNγ expression in both preparations as observed in control. Venom (50 μg/ml) caused 53.5 ± 8.5% and 55.8 ± 4.3% fiber damage in PND and BC, respectively; (n = 3, p < 0.05 vs. controls) and enhanced expression of TNFα and IFNγ. Pretreatment of the preparations with extract protected against venom-induced muscle damage by 80.3 and 60.4 in PND and BC, respectively, and prevented TNFα and IFNγ expression. These results indicate that the M. laevigata extract protected nerve-muscle preparations against the myotoxic, neurotoxic and inflammatory effects of P. olfersii venom.     

Antimutagenic effect of Phellinus rimosus (Berk) Pilat against chemical induced mutations of histidine dependent Salmonella typhimurium strains

Mutations are one of the important factors contributing to oncogenesis. Somatic mutations have been detected in oncogenes and tumor suppressor genes in various types of cancers. In vitro antimutagenic activity of ethyl acetate extract of macro fungus, Phellinus rimosus was evaluated by Ames’ mutagenicity assay. The effect was evaluated against the direct acting mutagens (sodium azide, N-methyl-N′-nitro-N-nitrosoguanidine, doxorubicin and 4-nitro-o-phenylenediamine) and mutagen needing activation (2-acetyl aminofluorine, and benzo[a]pyrene). The extract was significantly (p < 0.05) and dose dependently effective against direct acting mutagens and mutagen needing activation. Among the antimutagenic activity against directly acting mutagens, effect was found to be highest against doxorubicin-induced mutation. The antimutagenic effect of the extract against indirect acting mutagen in the presence of mammalian metabolic activation system was also found to be significant (p < 0.01). The background bacterial growth and number of revertant colonies in the extract alone treated plate with or with out metabolic activator was almost same as that of spontaneous revertants. This indicated the non-toxic nature of the extract. The effect was partially ascribed to the antioxidant activity. The results of the study suggest the possible antitumor mechanisms of P. rimosus.     

Role of vasoactive amines in the antitumor activity of endotoxin

To estimate a possible role of vasoamines in the antitumor action of endotoxin, effects of isoproterenol, serotonin and adrenaline on subcutaneosly transplanted murine Meth A sarcoma and the capacity of these agents to elicit antitumor factors were studied. Macroscopically all agents induced tumor necrosis and a temporal tumor growth stop, but only endotoxin was capable of induction of complete tumor regression. Histology showed that all agents induced hyperemia by 4 h and hemorrhagic necrosis by 24 h. The latter was located superficially at the outside of the tumors. Only serotonin and especially endotoxin induced substantial non-hemorrhagic necrosis in the remaining part of the tumors. Endotoxin induced a profound inhibition of the mitotic activity within the tumor, the effect of other agents was considerably less. Only endotoxin induced high levels of tumor necrosis factor, heat stable cytostatic factors and interferon in the circulation of mice treated with Corynebacterium parvum 14 days earlier.It is concluded that these and other data provide indirect but circumstantial evidence for a role of vasoamines in the induction of hyperemia and hemorrhagic necrosis by endotoxin. The latter two effects are probably causally related. It is suggested that non-toxic vasoamines may be useful adjuvants to other treatments of cancer.