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PubMedDate not supplied

Production of rotenone-inactivating substance(s) by rotenone-resistant insect cell line.

In a previous paper, we showed that a cell line derived from hemocytes of the cabbage armyworm, Mamestra brassicae (R-cell) was a thousand times as resistant to rotenone as that from ovaries of the same species (S-cell). The S-cells were killed by rotenone at concentrations higher than 10(-9) M, while R-cells at higher than 10(-6) M. When the R-cells were cultured in the medium containing 10(-9) M rotenone, the ability of rotenone to kill the S-cells was lost in the used medium. Also, when rotenone was incubated in the medium conditioned with R-cells, it lost its cell killing activity. It became evident that rotenone-inactivating substance(s) were produced in cells and stored in water-soluble form or liberated into the medium. The substance(s) were inactivated by heat treatment.

Animals↗
PubMed1993

Bioassay for carcinogenicity of rotenone in female Wistar rats.

Rotenone, a pesticide extracted from the Derris root, consistently was reported by a series of investigators to have induced mammary fibroadenomas in female Wistar rats when administered ip or by gavage in a sunflower (SF) oil or SF oil:chloroform vehicle. In contrast, no less than eight bioassays done in other laboratories with rotenone or rotenone-containing powders have given consistently negative carcinogenic results when different strains or species and different modes or vehicles of administration have been used. However, these studies were not designed to address the biological reproducibility of the positive data. Thus, the present study was designed to simulate conditions of the positive studies and to investigate a possible cocarcinogenic interaction between rotenone and chloroform. Each of eight treatment groups was assigned 72 weanling female Wistar rats. Groups were (1) untreated, (2) needle puncture, (3) SF oil:10% chloroform (SF oil:chloroform), (4) 1.0 mg/kg rotenone in SF oil:chloroform, (5) 2.0 mg/kg rotenone in SF oil:chloroform, (6) SF oil, (7) 1.0 mg/kg rotenone in SF oil, and (8) 2.0 mg/kg rotenone in SF oil. Rats were injected ip 5 days a week for 8 weeks (42 injection days) and subsequently held for 16 months. The appearance of palpable tissue masses was recorded; over 50 tissues from each rat were histologically evaluated. There were no statistically significant differences in overall or individual tumor incidences among control and rotenone-treated groups. Specifically, neither incidence nor time-to-palpation of mammary fibroadenoma significantly differed among control and rotenone-treated groups, regardless of the vehicle of administration. Thus, rotenone was not carcinogenic, and rotenone and chloroform did not interact to produce a carcinogenic effect in female Wistar rats in the current study. Thus, previous reports of carcinogenic activity were not reproducible under similar experimental conditions.

Adenocarcinoma↗
PubMed1994

Comparison of the inhibitory action of natural rotenone and its stereoisomers with various NADH-ubiquinone reductases.

Two stereoisomers of natural rotenone (5'alpha-epirotenone and 5'beta-epirotenone) were synthesized to identify the stereochemical factor of rotenone required for the inhibition and also to probe the structure of the rotenone binding site. The inhibitory action of the stereoisomers was compared with that of rotenone using NADH-ubiquinone reductases from bovine heart submitochondrial particles (SMP), potato tubers (Solanum tuberosum L.) SMP and Escherichia coli (GR19N) membranes. With respect to bovine heart SMP, it was found that the bent form of rotenone is essential for the activity. The modification of the E-ring moiety also affected both the inhibitory potency and the pattern of inhibition. These results indicated that the rotenone-binding site recognizes the whole molecular structure (or shape) of rotenone in a strict sense. Rotenone and 5'beta-epirotenone inhibited the NADH-ubiquinone reductase of bovine heart SMP in a noncompetitive manner against exogenous quinones. In contrast, the inhibition pattern of 5'alpha-epirotenone varied from noncompetitive to competitive as the concentration of quinone increased. These results suggest that rotenone binds close to, but not at a site identical to, the location for ubiquinone in the ubiquinone-catalytic reaction site, whereas the 5'alpha-epirotenone-binding site overlaps that for ubiquinone due to a structural modification of E-ring moiety. Furthermore, the complex inhibition pattern of 5'alpha-epirotenone suggests that there are two quinone-binding sites in NADH-ubiquinone reductase. In contrast, the order of the inhibitory potencies of the three inhibitors with proton-pumping NADH-ubiquinone reductase of potato SMP was the same as that observed for the bovine enzyme. This suggests that the structure of rotenone-binding sites (or ubiquinone-binding sites) of these enzymes are similar. It was further demonstrated that 5'alpha-epirotenone inhibits quinone binding to both proton-pumping and non-proton-pumping NADH-ubiquinone reductases of potato SMP in a competitive manner. With respect to the proton-pumping NADH-ubiquinone reductase of the E. coli membrane, the sensitivity of the enzyme to the inhibitor was remarkably decreased and the difference in the inhibitory potencies of the three inhibitors became ambiguous. In addition, the inhibition pattern of the three inhibitors was competitive against quinone. These results indicated that, contrary to the mammalian enzyme, only part of the rotenone molecule is recognized by the quinone-binding site of this enzyme.

Animals↗
PubMed1996

Structural factors of rotenone required for inhibition of various NADH-ubiquinone oxidoreductases.

We performed a structure-activity study of a series of synthetic rotenone analogues to elucidate the structural factors of rotenone required for inhibition and to probe the structural properties of the rotenone binding site of various NADH-ubiquinone oxidoreductases (NDH), including both proton-pumping (NDH-1) and non-proton-pumping (NDH-2) enzymes, from bovine heart mitochondria, potato tuber (Solanum tuberosum L.) mitochondria and Escherichia coli (GR 19N) plasma membranes. Using a benzyloxy group as a substitute for the E-ring moiety of natural rotenone, systematically selected structural modifications of the A-ring became feasible. The inhibitory potency of bovine NDH markedly varied depending upon structural modifications of the A-ring. The native chemical structure (2,3-dimethoxy substitution) appeared to be the most favorable for the activity. The spatial location of the hydrogen-bond acceptable methoxy oxygens may be important for tight fitting into the binding site. However, replacing one of the two methoxy groups by an ethoxy group almost completely retained the activity, indicating that the binding environment of the A-ring moiety is spacious enough to accommodate a substituent larger than the methoxy group. The manner of action of the derivative lacking the 12-C = O group in the C-ring differed from that of natural rotenone, indicating that this functional group is important for supporting the inhibitory action of natural rotenone itself. Regarding potato tube and E. coli NDH-1, the sensitivity of the two enzymes to the inhibition by rotenone analogues was much lower than that of the bovine enzyme. The 2,3-dimethoxy substitution was the most favorable for the activity with potato NDH-1, whereas this substitution pattern was not necessarily the best with E. coli NDH-1. A rule governing inhibitory potency depending upon structural modifications was ambiguous for the two enzymes because of a small variation in the inhibitory potencies. These findings indicated that the local binding environment of the A-ring moiety of rotenone in bovine NDH is specific and differs considerably from that in potato and E. coli NDH-1.

Animals↗
PubMed1997

Interaction of the mitochondrial NADH-ubiquinone reductase with rotenone as related to the enzyme active/inactive transition.

The interaction of rotenone with active ('pulsed') and thermally de-activated ('resting') membrane-bound Complex I (Kotlyar, A.B. and Vinogradov, A.D. (1990) Biochim. Biophys. Acta 1019, 151-158) as revealed by inhibition of NADH-ubiquinone- and ubiquinol-NAD+ reductase activities was studied. Ki = 1 x 10(-9) M, k(on) = 5 x 10(7) M-1 min-1 and k(off) = 0.02 min-1 (inhibitory effect of rotenone on NADH oxidation) and Ki = 2 x 10(-8) M (inhibition of reverse electron transfer) were determined for pulsed enzyme. The equilibrium between de-activated and active enzyme is reached (K approximately 100) after the slow strongly temperature-dependent de-activation process has completed. Rotenone partially prevents and reverses the enzyme de-activation. About two order of magnitude difference in affinity of rotenone to the active and de-activated forms of the enzyme was demonstrated. The strong difference in rotenone sensitivity of the direct and reverse reactions can not be accounted for delta mu H(+)-dependence of rotenone binding. We propose that two rotenone-specific inhibitory sites exist in Complex I: one is involved in NADH oxidation by ubiquinone and the other is operating in ubiquinol-NAD+ reductase reaction. The affinities of rotenone for both sites are strongly altered upon the slow enzyme active/inactive transition.

Animals↗
PubMed1996

The presence of rotenone-sensitive NADH dehydrogenase in the long slender bloodstream and the procyclic forms of Trypanosoma brucei brucei.

The mitochondrial electron-transport chain present in the procyclic and long slender bloodstream forms of Trypanosoma brucei brucei was investigated by means of several experimental approaches. The oxidation of proline, glycerol and glucose in procyclic cells was inhibited 80-90% by antimycin A or cyanide, 15-19% by salicylhydroxamic acid, and 30-35% by rotenone. Cytochrom-c-reductase activity, with proline or glycerol 3-phosphate as substrate, in a mitochondrial fraction isolated from these cells was inhibited by antimycin and rotenone, but not by malonate, while cytochrome-c-reductase activity with succinate as substrate was inhibited by antimycin A and malonate, but not by rotenone. In addition, the reduction of dichloroindophenol by NADH was inhibited by rotenone but not by malonate, which suggests that rotenone-sensitive NADH dehydrogenase (complex I) is present in these mitochondria. The presence of three subunits of NADH dehydrogenase was observed in immunoblots of mitochondrial proteins with specific antibodies raised against peptides corresponding to predicted antigenic regions of these proteins, which provides further evidence for the presence of NADH dehydrogenase. In long slender bloodstream forms, the oxidation of glucose or glycerol was inhibited 100% by salicyhydroxamic acid, unaffected by cyanide or antimycin A, and inhibited 40% or 75%, respectively, by rotenone, which suggests that NADH dehydrogenase is present in these cells. In a mitochondrial fraction isolated from the bloodstream forms, oxygen uptake with glycerol 3-phosphate as substrate was inhibited 65% by rotenone. Low levels of rotenone-sensitive NADH-dependent reduction of dichloroindophenol and the presence of subunits 7 and 8 of NADH dehydrogenase provided additional evidence for the presence of NADH dehydrogenase in bloodstream forms of T. brucei.

Animals↗
PubMed1982

Further characterization of the growth inhibitory effect of rotenone on in vitro cultured Ehrlich ascites tumour cells.

As an approach for a better understanding of the mode of action of rotenone on mammalian cells we have studied the proliferation properties, metabolism and basic cell composition of Ehrlich ascites tumour cells cultured in vitro in the presence of 2.5 microM rotenone and after removal of the inhibitor. Experiments on asynchronous cells showed a rapid cessation of cell division accompanied by increased glycolytic rate, reduced oxygen consumption, moderate increase in DNA content and a fair increase in protein and RNA content of the cultures. DNA histograms obtained by flow-cytometry revealed an accumulation of cells in the G2 and M phase of the cell cycle. Electron micrographs taken after a 24 h treatment of cells illustrated the formation of giant mitochondria and fragmented nuclei. In order to elucidate the dual effect of rotenone- inhibition of mitochondrial energy metabolism and of mitotic processes- the influence on cells of rotenone at different stages of the cell cycle was tested using Ehrlich ascites tumour cells enriched in G1, S and G2 by centrifugal elutriation. DNA histograms and [3H]thymidine labelling index curves of cells from the different fractions cultured in the presence of 2,5 microM rotenone indicated that in addition to the observed accumulation in G2 and mitotic arrest of cells, the cell cycle progression is delayed in G1 phase. This may be explained by an effect of the inhibitor on the respiratory chain. S phase cells seemed to continue the cycle for several hours at a rate comparable to that of controls. Recultivation experiments on rotenone-treated asynchronous cells in inhibitor-free medium confirmed that some cells reinitiate DNA synthesis without preceeding cell division. Thus it must be concluded that cells at all stages of the cycle are affected by rotenone, but the impairment of cellular metabolism becomes manifest and lethal as soon as the acute block at mitosis is abolished and cells reenter the cycle.

Animals↗
PubMed1983

Carcinogenesis with the insecticide rotenone.

Rotenone is an insecticide which has been used extensively for a long time, and is now widely used in the U.S.A. and other industrialized countries. Rotenone is used mainly as an agricultural insecticide, household garden insecticide and water plant pesticide. Through these uses, rotenone may now be reaching the human male and female in these countries in substantial amounts, carried by fresh or cooked vegetables, consumed fish and drinking water. A review of the existing published reports and unpublished official documents dealing with the capacity of rotenone to induce neoplastic, paraneoplastic and preneoplastic lesions in the rat is presented here. It is strongly suggested that rotenone is carcinogenic to the rat (at doses from 2 to 25 parts per million continuously in food, or from 0.8 to 2.5 mg/kg weight for 1 to 4 months by oral administration), above all, when the rats receive deficient diets, especially those poor in riboflavin. Rotenone carcinogenesis, among other things, seems to exhibit a peculiar dose response pattern, which could be explained by its possible hormonal mechanism of action. Further studies to assess definitively the role of rotenone as a possible environmental carcinogen are proposed as being highly necessary.

Animals↗
PubMed1997

Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone.

The effect of rotenone treatment on [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643) hepatic lesion growth in male B6C3F1 mice was investigated. Following induction of hepatic focal lesions by diethylnitrosamine (DEN) 35 mg/kg twice a week for 8 weeks, mice were placed into one of the four treatment groups: group I, control NIH-07 diet (control diet), group II, rotenone (600 mg/kg diet), group III NIH-07 diet containing WY-14,643 (1000 mg/kg diet), and group IV, NIH-07 diet containing WY-14,643 (1000 mg/kg diet) and rotenone (600 mg/ kg diet). Mice were killed after 30 and 60 days of dietary treatment. The effect of treatment with WY-14,643 and rotenone on hepatic lesion growth was examined by estimating the number of focal lesions per liver and the relative volume of focal lesions. WY-14,643 (group III) increased both the number and the volume of focal lesions. In particular, an increase in number and volume of basophilic lesions was seen. Co-treatment with WY-14,643 and rotenone (group IV) decreased both the number and the volume of the total number of focal lesions and basophilic foci compared with WY-14,643 treatment alone (group II). Alterations in the growth of hepatic focal lesions was further investigated by examining DNA synthesis and apoptosis within individual lesions. WY-14,643 (group III) treatment increased the DNA synthetic labeling index in all foci. Co-treatment of rotenone and WY-14,643 (group IV) decreased focal DNA synthesis and mitosis and increased the incidence of apoptotic hepatocytes. These data suggest that rotenone's ability to inhibit WY-14,643-induced hepatic focal lesion growth was mediated through a decrease in hepatic focal proliferation and an increase in focal apoptosis.

Adenoma↗
PubMed1988

Toxicity and carcinogenicity of rotenone given in the feed to F344/N rats and B6C3F1 mice for up to two years.

Toxicity and carcinogenicity studies of rotenone were conducted in F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given rotenone in their diet for up to 103 weeks. The doses were 0, 38, and 75 ppm for rats and 0, 600, and 1,200 ppm for mice. Reduction in body weight gain occurred in male and female mice given rotenone. No effects on survival were observed for rats of either sex or female mice. Survival of male mice at 1,200 ppm was significantly greater than that of controls (47/50 vs. 29/50). There were no observed nonneoplastic effects due to rotenone, and for male and female mice no neoplasms were induced by rotenone. Parathyroid adenomas occurred at a higher incidence (4/44) in male rats at 75 ppm than in the controls (1/41). Because these tumors are rare (historical rate in NTP studies is 0.3%), the increase in the incidence of these benign tumors may have been related to rotenone administration. Hepatocellular neoplasms were reduced (p less than 0.01) in males receiving 1,200 ppm 1/50 relative to controls 12/47. Because this low rate of liver tumors is unusual in male B6C3F1 mice, this decrease was considered to be related to rotenone administration.

Animals↗
PubMed1979

Failure of rotenone to interfere with 17 beta-estradiol action in the rat uterus.

The involvement of rotenone in rat mammary carcinogenesis has been suggested to occur through estrogenic effects. This hypothesis was tested by determining the extent of rotenone inhibition of 17 beta-estradiol binding to the estrogen receptor and of the 17 beta-estradiol-induced uterotrophic response in ovariectomized Sprague-Dawley rats. Estradiol binding to the uterine estrogen receptor in the presence of rotenone was determined by charcoal assay and Scatchard analysis. Additionally, 17 beta-estradiol-receptor interactions were assessed on sucrose density gradients. No inhibition of binding was observed in either assay with ratios of rotenone/17 beta-estradiol in excess of 10,000. Finally, an in vivo approach was used to extend the in vitro data. Silastic capsules containing rotenone or 17 beta-estradiol were implanted in various combinations into eight groups of ovariectomized Sprague-Dawley rats (four rats/group). After five days, uteri were removed and weighed. An analysis of variance revealed that rotenone neither interfered with 17 beta-estradiol-induced uterine weight gain nor displayed any uterotrophic properties by itself. Results from these three procedures demonstrate that rotenone does not act as an estrogen or as an estrogen antagonist. Additionally, there were no other effects attributable to rotenone.

Animals↗
PubMed1991

Succinate-driven reverse electron transport in the respiratory chain of plant mitochondria. The effects of rotenone and adenylates in relation to malate and oxaloacetate metabolism.

The effects of rotenone on the succinate-driven reduction of matrix nicotinamide nucleotides were investigated in Percoll-purified mitochondria from potato (Solanum tuberosum) tubers. Depending on the presence of ADP or ATP, rotenone caused an increase or a decrease in the level of reduction of the matrix nicotinamide nucleotides. The increase in the reduction induced by rotenone in the presence of ADP was linked to the oxidation of the malate resulting from the oxidation of succinate. Depending on the experimental conditions, malic enzyme (at pH 6.6 or in the presence of added CoA) or malate dehydrogenase (at pH 7.9) were involved in this oxidation. At pH 7.9, the oxaloacetate produced progressively inhibited the succinate dehydrogenase. In the presence of ATP the production of oxaloacetate was stopped, and succinate dehydrogenase was protected from inhibition by oxaloacetate. However, previously accumulated oxaloacetate transitorily decreased the level of the reduction of the NAD+ driven by succinate, by causing the reversal of the malate dehydrogenase reaction. Under these conditions (i.e. presence of ATP), rotenone strongly inhibited the reduction of NAD+ by succinate-driven reverse electron flow. No evidence for an active reverse electron transport through a rotenone-insensitive path could be obtained. The inhibitory effect of rotenone was masked if malate had previously accumulated, owing to the malate-oxidizing enzymes which reduced part or all of the matrix NAD+.

Adenosine Diphosphate↗
PubMed1996

Rotenone, a mitochondrial NADH dehydrogenase inhibitor, induces cell surface expression of CD13 and CD38 and apoptosis in HL-60 cells.

We previously demonstrated that the mitochondrial NADH dehydrogenase subunit 2 (ND2) gene was overexpressed in human acute myelogenous leukemia (AML) cells. Since this finding suggested that ND2 gene expression was related to myeloid differentiation, we here investigated the effects of rotenone, a specific NADH dehydrogenase inhibitor, on HL-60 cell growth, differentiation and death. Fifty nM rotenone inhibited the growth of HL-60 cells and caused an increase in the cell population in the G(2) +M phase. In the quantitative comparison of myeloid antigen, the expression of CD13 and CD38 were relatively increased in the rotenone-treated cells. These findings suggest that the inhibition of NADH dehydrogenase changes the cell cycle and induces some specific surface antigens of HL-60 cells. On the other hand, the expression of ND2 gene remained unchanged after the rotenone treatment, suggesting the rotenone-mediated mitochondrial inhibition did not affect the mitochondrial gene expression. Five mu M rotenone strongly inhibited the cellular proliferation. Electron microscopy and an electrophoretic analysis of DNA showed that the majority of the HL-60 cells were induced into typical apoptosis within 24-48 hours. On the basis of this and other studies, we believe that mitochondrial function is directly involved in both cellular differentiation and apoptotic cell death.

ADP-ribosyl Cyclase↗
PubMed1990

The measurement of the rotenone-sensitive NADH cytochrome c reductase activity in mitochondria isolated from minute amount of human skeletal muscle.

Mitochondria isolated from minute amounts (100-500 mg) of human skeletal muscle displayed a very high rotenone-resistant NADH cytochrome c reductase activity. Moreover, compared to succinate cytochrome c reductase activity, a low rate of rotenone-sensitive NADH cytochrome c reductase activity was measured when using standard procedures to disrupt mitochondrial membranes. Only a drastic osmotic shock in distillated water as a mean to disrupt mitochondrial membrane was found to strongly increase the actual rate of the rotenone-sensitive activity. This was accompanied by a decrease in the rotenone-insensitive activity. Using such a simple procedure, the NADH cytochrome c reductase was found 70-80% inhibited by rotenone and roughly equivalent to 70-85% of the activity of the succinate cytochrome c reductase.

Cell Fractionation↗
PubMedDate not supplied

Oxidation of rotenone by Polyporus anceps laccase.

The extracellular laccase produced by Polyporus anceps transforms rotenone to a single, more polar product. This transformation occurs in incubation mixtures containing chlorpromazine, laccase, and rotenone where rotenone serves as a pseudosubstrate for the enzyme. Chlorpromazine, the true substrate, serves as a cycling redox component of the system forming a radical-cation species that abstracts an electron from rotenone in the oxidation process. Physicochemical properties of the product were determined on an analytically pure sample obtained by preparative hplc. High resolution ms, high-field pmr and cmr, uv, and optical rotation analyses indicated that rotenone had been transformed to 6a beta, 12a beta-rotenolone by P. anceps laccase.

Basidiomycota↗
PubMed1982

Regulation of malate oxidation in plant mitochondria. Response to rotenone and exogenous NAD+.

Exogenous NAD+ stimulated the rotenone-resistant oxidation of all the NAD+-linked tricarboxylic acid-cycle substrates in mitochondria from Jerusalem artichoke (Helianthus tuberosus L.) tubers. The stimulation was not removed by the addition of EGTA, which is known to inhibit the oxidation of exogenous NADH. It is therefore concluded that added NAD+ gains access to the matrix space and stimulates oxidation by the rotenone-resistant NADH dehydrogenase located on the matrix surface of the inner membrane. Added NAD+ stimulated the activity of malic enzyme and displaced the equilibrium of malate dehydrogenase; both observations are consistent with entry of NAD+ into the matrix space. Analysis of products of malate oxidation showed that rotenone-resistant oxygen uptake only occurred when the concentration of oxaloacetate was low and that of NADH was high. Thus it is proposed that the concentration of NADH regulates the activity of the two internal NADH dehydrogenases. Evidence is presented to suggest that the rotenone-resistant NADH dehydrogenase is engaged under conditions of high phosphorylation potential, which restricts electron flux through the rotenone-sensitive dehydrogenase (coupled to ATP synthesis).

Adenosine Diphosphate↗