Deposition of esfenvalerate on Brassica vegetables.
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Brassica↗
Biomedical subjects
L O Lim
Publications and source records attributed to L O Lim.
Irreversible inhibition of the cytosolic metabolism of N-hydroxy-2-acetylaminofluorene by its glycolyl analog.
The glycolyl hydroxamic acid derivative of 2-aminofluorene was found to be a potent inhibitor of its own metabolism and the metabolism of N-hydroxy-2-acetylaminofluorene by rat liver cytosol. The inhibition was irreversible, as well as time and concentration dependent, which indicates a suicide-inhibition type of metabolism. There was a direct correlation between the inhibition of N-hydroxy-2-acetylaminofluorene disappearance and 2-acetylaminofluorene formation. In contrast, both the glycolyl and acetyl hydroxamic acid derivatives were metabolized to a similar extent by enzymes in the microsomal fraction.
2-Acetylaminofluorene↗
Mitochondrial DNA damage by bleomycin.
We have modified a specific and sensitive method of detecting different forms of mitochondrial DNA (mtDNA) and utilized it to study bleomycin (BLM)-induced mtDNA damage. Intact, nicked circular, and linear forms of mtDNA were separated by gel electrophoresis, detected by Southern blot hybridization, and characterized by size markers and alkali treatment. DNA from BLM-treated mitochondria from liver, lung, and L1210 tumors were all equally sensitive to damage by BLM. The extent of BLM-induced mtDNA damage was dependent on experimental conditions. In vitro incubation of isolated mitochondria with BLM showed that 100 microM BLM caused complete conversion of intact to nicked and linear forms. Scission of mtDNA was more extensive if mitochondria were lysed in the presence of BLM than after several washings to remove the drug from the incubation media. Isolated mtDNA was extremely sensitive to BLM such that 10 nM BLM caused loss of intact form. The extent of mtDNA damage by BLM was decreased by the addition of EDTA.
Animals↗
Nitrofurantoin inhibition of mouse liver mitochondrial respiration involving NAD-linked substrates.
In our study, nitrofurantoin (NF) and nitrofurazone (NZ) inhibited respiration of isolated mouse (C57B/6J, adult, male) liver mitochondria. Other aromatic nitro compounds, nitroimidazole, metronidazole, and p-nitrobenzoic acid, did not have any significant effect. The primary site of activity for NF was complex I NADH-ubiquinone oxidoreductase mediated respiration, since only complex I substrates, glutamate, beta-hydroxybutyrate, and alpha-ketoglutarate-mediated respiration were decreased. Respiration supported by succinate, a complex II substrate, was not affected by any of the compounds. NF at a concentration of 50 microM decreased state 3 and dinitrophenol-uncoupled respiration to 28 +/- 1 and 25 +/- 5% of control, respectively, of mitochondria oxidizing glutamate. Studies with mitoplasts oxidizing glutamate showed that NF inhibited both state 3 and 4 respiration. The inhibition of state 3 was prevented by the simultaneous addition of superoxide dismutase (240 micrograms/ml) and catalase (200 micrograms/ml). These results suggest that the mitochondrion, in particular complex I of the electron transport system, is a target for NF toxicity. The effect on respiration may be mediated by NF redox cycling and the generation of reactive oxygen intermediates resulting in the interference of electron flow.
Animals↗
DNA damage induced by chloramphenicol and nitroso-chloramphenicol: protection by N-acetylcysteine.
We have previously demonstrated that nitroso-chloramphenicol (NO-CAP) in small concentrations causes the hydrolysis of isolated double stranded DNA in vitro and this action is blocked by sulfhydryl groups. The present study was designed to assess damage to isolated DNA as well as intact cells DNA and examine the protective effect of N-acetylcysteine (NAC). Using alkaline sucrose gradient sedimentation and the alkali elution technique of Kohn we were able to demonstrate DNA damage in Raji cells as well as phytohemagglutinin stimulated human lymphocytes after exposure to NO-CAP. Damage could be totally blocked by NAC. In preliminary studies we also observed that NAC protects bone marrow cells from the growth-inhibitory effects of chloramphenicol and thiamphenicol.
Acetylcysteine↗
Comparative effects of selected drug combinations on the growth of a human pancreatic carcinoma cell line (MIA PaCa-2).
The inhibitory effect of several drug combinations on the growth of the human pancreatic carcinoma cell line MIA PaCa-2 was studied in relation to drug-scheduling interval in vitro. All drug exposures were for 1 hour. The sequential exposure of cells to 1.5 X 10(-8) M vincristine (VCR) or vindesine (VDS) followed by 2 X 10(-8) M 1,2-dihydroxy-9,10-anthracenedione (DHAD) or 3 X 10(-7) M adriamycin (ADR) had at best an additive effect, demonstrated by isobologram analysis, when the two drugs were given 6 hours apart. Flow cytometry (FCM) analysis after exposure of the cells to the priming drug alone, i.e., VCR or VDS, showed an accumulation of cells in S-phase. The exposure of MIA PaCa-2 cells to 1.6 X 10(-5) M 5-fluorouracil (FUra) followed by 2 X 10(-8) M DHAD or 3 X 10(-7) M ADR had an additive (with DHAD) or synergistic (with ADR) effect when the two drugs were given simultaneously and a synergistic effect with either drug when they were given 2, 6, or 24 hours apart. FCM analysis after exposure to FUra alone showed a rapid S-phase accumulation appearing within 6 hours and increasing further after 24 hours. Sequential exposure of cells to 1.5 X 10(-8) M VCR and 1.6 X 10(-5) M FUra had a synergistic effect, regardless of the sequence or the time interval between the two drugs.
Anthraquinones↗
Effects of ticlopidine, a new platelet antiaggregating agent, and its analogues on mitochondrial metabolism. Oxidative phosphorylation, protein synthesis and DNA polymerase activity.
The effects of ticlopidine and six of its analogues on mitochondrial functions were studied in isolated rat liver mitochondria. The influence of ticlopidine and each of the following analogues: PCR 5325, PCR 4099, PCR 3787, PCR 2362, PCR 4499 and PCR 0665 was evaluated by determining their interaction with three major mitochondrial activities. (A) Oxidative phosphorylation, measured by oxypolarography, was assayed in the presence of glutamate or succinate as source of energy, and both State 4 and State 3 were recorded. Ticlopidine, at 20 micrograms/ml, slightly increased glutamate State 4, whereas it was without effect on that of succinate. At higher concentration (40 micrograms/ml), ticlopidine caused 40-45% inhibition of State 4 with both substrates. All the other analogues tested at either 20 or 40 micrograms/ml were virtually without effect on the respiration. However, at 20 micrograms/ml, ticlopidine and some of its analogues inhibited mitochondrial State 3, while under similar conditions other analogues had little or no effect on this state. (B) Mitochondrial protein synthesis, measured by [14C]-L-leucine incorporation, was not affected significantly by any of these drugs. Whereas chloramphenicol at 10 micrograms/ml caused 80% inhibition, ticlopidine and its analogues in concentrations inhibitory to State 3 did not inhibit mitochondrial protein synthesis. (C) Mitochondrial DNA polymerase activity, determined by [3H] thymidine 5'-triphosphate incorporation, was not inhibited by these drugs. We conclude that, while ticlopidine and analogues have little or no effect on either mitochondrial protein synthesis or mitochondrial DNA polymerase activity, ticlopidine and some of its analogues are inhibitory of the energy conserving mechanism in mitochondria.
Animals↗
Sensitivity of cultured human pancreatic carcinoma cells to dihydroxyanthracenedione.
We tested the effectiveness of dihydroxyanthracenedione (DHAD) on cell growth of two human pancreatic carcinoma cell lines MIA PaCa-2 and PANC-1. At the level of ID50, the drug was almost equally effective against both cell lines. When the time exposure of MIA PaCa-2 cells to the drug was increased from 1 h to continuous exposure for 5 days, the ID50 was decreased about three-fold only (1.4 X 10(-8)M and 4 X 10(-9)M respectively). At the level of ID50 also the difference between 6 h exposure and continuous exposure for 5 days was minimal. In equimolar concentrations and with 1 h exposure, DHAD was more effective against MIA PaCa-2 cells than other chemotherapeutic agents including adriamycin, mitomycin-C, 5-FU, vincristine, vindesine, vinblastine, VP-16-213, bleomycin, cis-platinum, asparaginase and acivicin. In concentrations of 5 X 10(-7)M, DHAD caused about 40% inhibition of 14C-thymidine incorporation of MIA PaCa-2 cells. Treatment of MIA PaCa-2 cells with the ID50 of DHAD for 1 h caused retardation of cellular traverse, with the major effect appearing to be in G2 + M phase of the cycle. From these data DHAD appears to be a potent drug against human pancreatic carcinoma in vitro.
Anthraquinones↗
Sensitivity of human pancreatic carcinoma cell line (MIA PaCa-2) to Bisantrene and Theprubicin in vitro.
We tested the effect of Bisantrene (BS) and Theprubicin (THP-ADR) on cell growth of a human pancreatic carcinoma cell line (MIA PaCa-2). After 1 h exposure ID50 of BS or THP-ADR was 3 X 10(-7) and 5 X 10(-8) M, respectively. Increasing the exposure time from 1 h to continuous exposure for 5d resulted in 11-fold decrease in ID50 for BS and a 6-fold decrease for THP-ADR. Both drugs inhibited [14C]thymidine incorporation to the same extent and caused an accumulation of cells into G2 + M phase of the cell cycle.
Anthracenes↗
The effect of nitroso-chloramphenicol on mitochondrial DNA polymerase activity.
We studied the effects of nitroso-chloramphenicol, chloramphenicol, amino-chloramphenicol, and thiamphenicol on the activity of mitochondrial DNA polymerase of rat liver. 3H-thymidine triphosphate incorporation into DNA was used to measure the DNA polymerase activity in the mitochondrial matrix fraction. This fraction was in the supernatant of sonicated mitochondria obtained by ultracentrifugation. Under standard experimental conditions, thymidine triphosphate incorporation was time dependent up to 10 minutes. This activity was enhanced by beta-mercaptoethanol and was blocked by the known polymerase inhibitors ethidium bromide and 2',3'-dideoxythymidine 5'-triphosphate. Chloramphenicol and its analogues, amino-chloramphenicol and thiamphenicol, did not have a significant effect on the polymerase activity, whereas nitroso-chloramphenicol was inhibitory. The degree of inhibition was dependent on the experimental conditions. Thus, in the absence of beta-mercaptoethanol, nitroso-chloramphenicol caused inhibition; however, in its presence, there was no significant inhibitory effect. Under similar conditions, the addition of dithiothreitol also provided partial protection. On the other hand, the inhibition by nitroso-chloramphenicol was significantly enhanced with its preincubation in the mitochondrial matrix fraction before the addition of nucleotides and DNA; thus after 40 minutes of preincubation, nitroso-chloramphenicol at a concentration of 200 mumol/L gave 53% inhibition, and produced total inhibition at 600 mumol/L. The addition of NADH or NADPH to the preincubation medium produced substantial protection against nitroso-chloramphenicol, whereas nicotinamide-adenine dinucleotide had no effect. These results suggest that mitochondrial DNA polymerase may be a target for nitroso-chloramphenicol action. The potentiation of that action by preincubation and the protection against it by NADH and NADPH suggest the involvement of intermediate metabolic steps for maximal inhibition.
Animals↗
Enzymatic reduction of chloramphenicol and nitrosochloramphenicol by rat liver microsomal preparations.
Chloramphenicol (CAP) and nitrosochloramphenicol (NO-CAP) were metabolically reduced to aromatic amines by rat liver microsomes in vitro. The reduction required anaerobic conditions and was mediated by a NADPH-dependent reductase system. Both CAP and NO-CAP reduction were time and concentration dependent. Compared to CAP, NO-CAP (0.5 mM) reduction was rapid with complete conversion occurring in 90-120 min. At 2.5 mM NO-CAP reduction was depressed. In the presence of NO-CAP (0.05-2.5 mM) CAP metabolism was inhibited from 17 to 91%. These results indicate that CAP and NO-CAP are metabolized by similar microsomal reductase systems and NO-CAP is unstable, readily reduced further to the aromatic amine.
Animals↗
Induction of methemoglobin formation by nitroso-chloramphenicol in hemolyzed blood.
We studied the effects of chloramphenicol (CAP), nitroso-chloramphenicol (NO-CAP) and thiamphenicol (TAP) on methemoglobin (MeHb) formation in vitro in hemolyzed blood. At concentrations of 0.5 to 10 mM CAP and TAP did not have any effect on hemoglobin. On the other hand, NO-CAP at 0.25 to 5 mM caused both time and concentration dependent increase in MeHb formation. The oxidation of hemoglobin was reversible by potassium cyanide. Since MeHb was detected only at NO-CAP concentration 0.25 mM or higher, methemoglobin formation is not a sensitive indication of NO-CAP presence.
Chloramphenicol↗
Marine bivalves, particularly mussels, Mytilus sp., for assessment of environmental quality.
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Animals↗
Herbicidal potency of 1,1'-alkyl-4,4'-bipyridylium salts as a function of their physicochemical constants in duckweed.
Duckweed (Spirodela oligorrhiza, Kurz) is a sensitive indicator of 1,1'-alkyl-4,4'-bipyridylium salt (viologen) herbicidal potency. A homologous series of viologens were tested to determine relative herbicidal potency which was related to alkyl inductive and steric effects of N-alkyl side chains. Chlorosis was assessed after 48 hr of continuous illumination to establish herbicidal potency. Herbicidally effective concentrations were 2.7, 12, 236, 71, 31, 51, 13 and 43 microM for methyl (paraquat), propyl, isopropyl, butyl, methyl-pentyl, hexyl, octyl and benzyl viologen, respectively. A biphasic relationship of herbicidal potency versus steric effect was established in which compounds with the least bulky side chains were most phytotoxic. Comparison of rat lethality (acute, subcutaneous) and herbicidal potency of these compounds indicates that none of the viologens tested are less toxic to mammals than plants compared to the commercial herbicide methyl biologen (paraquat).
Animals↗
Covalent binding of N-hydroxy-N-acetyl-2-aminofluorene and N-hydroxy-N-glycolyl-2-aminofluorene to rat hepatocyte DNA: in vitro and cell-suspension studies.
Two 2-aminofluorene-derived hydroxamic acids that differ only in the nature of the N-acyl group were examined for their relative abilities to undergo covalent binding to nucleic acids. Studies of the bioactivation of N-hydroxy-N-acetyl-2-aminofluorene (N-OH-AAF) and N-hydroxy-N-glycolyl-2-aminofluorene (N-OH-GAF) were conducted with hepatocyte suspensions and subcellular fractions prepared from male Sprague-Dawley rats. Both hydroxamic acid substrates displayed equal binding to both DNA and RNA after incubations with hepatocyte suspensions. The extent of binding of each substrate was approximately the same for DNA and RNA. Investigations with subcellular fractions revealed some major differences between the probable mechanisms by which the two substrates were covalently bound to exogenous DNA. In agreement with the prior literature reports, N-OH-AAF was extensively bound to DNA through the action of cytosol enzymes, including both N,O-acyltransferase and sulfotransferase. The microsomal enzyme fraction also catalyzed binding to DNA, and this process was completely inhibited by paraoxon. The covalent binding of N-OH-GAF to DNA was catalyzed by cytosol enzymes to a significant extent only in the presence of 3'-phosphoadenosine-5'-phosphosulfate, which suggests the action of sulfotransferase. Covalent binding of N-OH-GAF to DNA was minimal through the action of cytosolic N,O-acyltransferase, which confirms our earlier observation that N-OH-GAF is a potent suicide inhibitor of this enzyme. The microsomal fraction catalyzed the binding of N-OH-GAF to DNA at a rate that was about twice that observed for N-OH-AAF.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The inhibitory effects of teniposide and homoharringtonine on the growth of pancreatic carcinoma cells in vitro.
The inhibitory effect of VM-26 and Homoharringtonine (HHT) on the in vitro growth of a human pancreatic cell line (MIA PaCa-2) was tested. The ID50 of VM-26 and HHT was 6 x 10(-7) M and 2 x 10(-5) M respectively. Increasing time exposure from 1 hr to continuous exposure for 5 days resulted in a 30-fold decrease in ID50 for VM-26 and a 2,000-fold decrease for HHT. 14C-labelled thymidine and leucine studies revealed that VM-26 inhibited DNA synthesis, while HHT inhibited both DNA and protein synthesis.
Alkaloids↗