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At least 19 recordsLinked to original sources
PubMed1999

FLR1 gene (ORF YBR008c) is required for benomyl and methotrexate resistance in Saccharomyces cerevisiae and its benomyl-induced expression is dependent on pdr3 transcriptional regulator.

In this work we report the disruption of a Saccharomyces cerevisiae ORF YBR008c (FLR1 gene) within the context of EUROFAN (EUROpean Functional Analysis Network) six-pack programme, using a PCR-mediated gene replacement protocol as well as the results of the basic phenotypic analysis of a deletant strain and the construction of a disruption cassette for inactivation of this gene in any yeast strain. We also show results extending the knowledge of the range of compounds to which FLR1 gene confers resistance to the antimitotic systemic benzimidazole fungicide benomyl and the antitumor agent methotrexate, reinforcing the concept that the FLR1 gene is a multidrug resistance (MDR) determinant. Our conclusions were based on the higher susceptibility to these compounds of flr1Delta compared with wild-type and on the increased resistance of both flr1Delta and wild-type strains upon increased expression of FLR1 gene from a centromeric plasmid clone. The present study also provides, for the first time, evidence that the adaptation of yeast cells to growth in the presence of benomyl involves the dramatic activation of FLR1 gene expression during benomyl-induced latency (up to 400-fold). Results obtained using a FLR1-lacZ fusion in a plasmid indicate that the activation of FLR1 expression in benomyl-stressed cells is under the control of the transcriptional regulator Pdr3p. Indeed, PDR3 deletion severely reduces benomyl-induced activation of FLR1 gene expression (by 85%), while the homologous Pdr1p transcription factor is apparently not involved in this activation.

4-Nitroquinoline-1-oxide↗
PubMed1990

Inhibitory effects of benomyl and carbendazim on the [3H]thymidine incorporation in various organs of the mouse--evidence for a more pronounced action of benomyl.

The benzimidazole fungicides benomyl and carbendazim were compared with regard to effects on [3H]thymidine incorporation in various organs of male mice given the compounds orally at various time intervals before sacrifice. Since carbendazim is a major metabolite of benomyl, it is generally assumed that the fungicidal action and toxicity of these compounds are due to the action of carbendazim. However, whereas benomyl inhibited the [3H]thymidine incorporation into thymus, spleen, liver, kidney and testis, an equimolar amount (3.4 mmol/kg body wt) of carbendazim induced a similar effect only in testis.

Animals↗
PubMed1997

The role of the benomyl metabolite carbendazim in benomyl-induced testicular toxicity.

The present study has investigated the role of benomyl (BNL) vs carbendazim (CBZ) in BNL-induced testicular toxicity. Equivalent molar concentrations of BNL and CBZ were administered to rats intraperitoneally (859 mumol/kg) or by direct injection into the testis (1.37 mumol/testis). Whereas no significant testicular damage was observed both 1 and 2 hr after BNL administration by the ip route, CBZ administration resulted in sloughing of the seminiferous epithelium after 1 hr, which increased in severity at the 2-hr time point. Intratesticular treatment of BNL caused little testicular damage after 1 hr whereas an equimolar amount of CBZ elicited severe disruption of the seminiferous epithelium. Testicular levels of CBZ and BNL were measured at various times after both routes of administration. The AUC from the concentration of CBZ in the testis vs time plot showed an excellent relationship to the number of tubules which exhibited slouging. The BNL AUC also showed a straight-line relationship to severity of lesion. However, when the contribution of CBZ to the BNL response was subtracted, no effect of BNL was discernible. The effect of BNL and CBZ on testicular microtubule assembly was then investigated. IC50 for CBZ was 5 microM and that for BNL was 75 microM. Again, the effect of BNL on microtubule assembly could be largely accounted for by the presence of the CBZ breakdown product. These results strongly suggest that the BNL metabolite CBZ, and not BNL itself, is the mediator of BNL-induced testicular toxicity and inhibitor of testicular microtubule assembly.

Animals↗
PubMed2001

Characterizing the production of a wild-type and benomyl-resistant Fusarium lateritium for biocontrol of Eutypa lata on grapevine.

Benomyl-resistant (BR) and wild-type (WT) strains of Fusarium lateritium were examined for their tolerance to benomyl on potato dextrose agar (PDA) containing benomyl and control of the Eutypa lata in grapevine bioassays. The WT strain grew on PDA containing 1 microg/ml benomyl at 13, 26 and 29 degrees C. The BR strain grew on PDA containing 10 microg/ml benomyl at 4 degrees C, on PDA containing 100 microg/ml benomyl at 29 degrees C, and on PDA containing 1,000 microg/ml benomyl at 13 degrees C and 26 degrees C. The BR strain was also able to colonize grapevine segments and control E. lata in the presence of 1,000 microg/ml benomyl. Both strains were amenable to production via liquid fermentation and both achieved 100% control of E. lata in grapevine bioassays. Neither the duration of fermentation nor incubation temperature during grapevine bioassays influenced the efficacy of either strain against E. lata. The results suggest that application of BR F. lateritium alone or in combination with benomyl may provide good control of E. lata.

Ascomycota↗
PubMed1983

Reproductive toxicity of methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) in male Wistar rats.

Methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) is a systemic fungicide which has been implicated in producing damage to the testes. The present investigation was undertaken to evaluate the functional and behavioral significance of this reported benomyl-induced damage to male rats using a 70-day feeding study followed by a 70-day recovery study. Adult male Wistar rats were fed laboratory chow containing 1.0, 6.3, or 203 ppm benomyl, with control animals receiving standard laboratory chow. Ejaculate sperm counts were significantly depressed (P less than or equal to 0.05) in male ingesting 203 ppm benomyl during the 70 day feeding phase. A significant decrease in relative testicular weights and a lowered male fertility index were observed in all benomyl-treatment groups. No significant alterations in plasma testosterone, LH, or FSH levels were observed during the feeding phase. Benomyl ingestion did not alter male copulatory behavior, nor was benomyl found to be an inducer of dominant lethal mutations. Identical studies performed during the recovery phase demonstrated that the benomyl-induced alterations in testicular function were reversible. The male fertility index, ejaculate sperm content, and testicular weights returned to control values during this phase.

Animals↗
PubMed1998

Mechanism for benomyl action as a mitochondrial aldehyde dehydrogenase inhibitor in mice.

Benomyl (a non-thio fungicide) inhibits hepatic mitochondrial low-Km aldehyde dehydrogenase (mALDH or ALDH2) in ip-treated mice by 50% (IC50) at 7.0 mg/kg, which is surprisingly the same potency range as that for several dithiocarbamate fungicides (and the related alcohol abuse drug disulfiram) and thiocarbamate herbicides previously known for their alcohol-sensitizing action. The mechanism by which benomyl inhibits mALDH was therefore examined, first by comparing the metabolism of benomyl with the aforementioned mono- and dithiocarbamates and second by evaluating the inhibitory potency of the benomyl metabolites. Benomyl in ip-treated mice is converted, via butyl isocyanate, S-(N-butylcarbamoyl)glutathione, and S-(N-butylcarbamoyl)cysteine, to S-methyl N-butylthiocarbamate (MBT), identified as a transient metabolite in liver. MBT is >10-fold more potent than benomyl or butyl isocyanate as an in vivo mALDH inhibitor and is also more potent than the intermediary S-(N-butylcarbamoyl) conjugates. Benomyl and MBT inhibit mouse hepatic mALDH in vitro with IC50s of 0.77 and 8.7 microM, respectively. The potency of MBT is greatly enhanced by fortification of the mitochondria with NADPH alone or plus microsomes giving IC50s of 0.50 and 0.23 microM, respectively. This activation of MBT is almost completely blocked by the cytochrome P450 inhibitor N-benzylimidazole but not by several other cytochrome P450 inactivators. MBT (probably following bioactivation) inhibits mALDH in vivo with an IC50 of 0.3 mg/kg. Two candidate activation products were synthesized for potency determinations. N-Hydroxy MBT (prepared via the trimethylsilyl derivative) was not detected as an MBT metabolite; its low potency also rules against N-hydroxylation as the activation process. MBT sulfoxide, from oxidation of MBT with magnesium monoperoxyphthalate in water, is one of the most potent inhibitors known for mALDH and yeast ALDH in vitro (IC50 0.08-0.09 microM). These findings are consistent with a six-step bioactivation of benomyl, via the metabolites above and N-butylthiocarbamic acid, with MBT as the penultimate and MBT sulfoxide as the ultimate inhibitor of mALDH.

Aldehyde Dehydrogenase↗
PubMed1991

Effects on the fetal rat eye of maternal benomyl exposure and protein malnutrition.

Benomyl, a benzimidazole fungicide, produced ocular and craniocerebral malformations in fetal rats when administered to the dams by gavage in a dose of 62.4 mg/kg of maternal body weight/day on days 7-21 of gestation. Ocular anomalies included retinal dysplasia, cataracts, microphthalmia, and anophthalmia. These anomalies occurred in 43.3% of fetuses exposed to benomyl and a normal protein diet but increased to 62.5% when benomyl administration was combined with a protein deficient (8% casein) diet. Microscopic examination of the malformed eyes revealed that the most common abnormality, retinal dysplasia, consisted of rosettes of retinal cells and retinal infolding. The majority of rosettes had a single layer and a limiting membrane. Rosettes with two or three layers were also observed, particularly in fetuses exposed both to protein deficiency and benomyl. Although anophthalmia was identified macroscopically in five fetuses, only a single instance of true anophthalmia was found microscopically. These data support the results of previous investigators that benomyl induces ocular malformation and that protein deficiency enhances the teratogenic effects of benomyl. The disorderly proliferation of retinal cells and rosette formation resembled the periventricular cell masses that accumulate in brains exposed to benomyl and certain other teratogenic agents. The anti-tubulin action of benomyl is known to impair microtubule formation and it may produce brain and ocular malformations by disruption of neuronal proliferation and migration.

Abnormalities, Drug-Induced↗
PubMed1987

Benomyl-induced craniocerebral anomalies in fetuses of adequately nourished and protein-deprived rats.

Benomyl, a benzimidazole fungicide, produced craniocerebral and systemic malformations in fetal rats when administered by gavage in doses of 31.2, 62.5, and 125 mg/kg of maternal body weight on days 7-21 of gestation. Malformations increased in incidence and severity with increasing benomyl dosage and nearly doubled when coupled with a protein-deficient diet. Protein deficiency alone produced only decreased fetal weight. High benomyl doses produced higher percentages of fetal resorptions and late fetal deaths, and these percentages also increased with protein deficiency. A benomyl dose of 62.5 mg/kg in protein-deficiency dams, the optimal combination for a high incidence of anomalies and low fetal wastage, produced hydrocephalus in 69.4% of fetuses, meningocele in 8.2%, encephalocele in 14.3%, exencephaly in 44.9%, anencephaly in 14.3%, corpus callosum agenesis in 26.5%, periventricular necrosis in 26.5%, and periventricular cellular "overgrowth" in 55.1%. The most common combination of anomalies was hydrocephalus, exencephaly, and periventricular "overgrowth." Common systemic malformations included cleft palate, micromelia, hydroureter, and misshapen tails. No fetus was entirely normal at the highest benomyl dose. Benomyl has been shown by others to bind tubulin and inhibit the formation of microtubules that are important in neurulation, mitosis, and cell migration during early brain development. Thus, it is suggested that benomyl, coupled with a protein-deficient diet, offers a teratogenic model with a spectrum of abnormalities similar to hypervitaminosis A but with a higher yield of specific craniocerebral anomalies.

Animals↗
PubMed2001

Transcriptional activation of FLR1 gene during Saccharomyces cerevisiae adaptation to growth with benomyl: role of Yap1p and Pdr3p.

The adaptation of Saccharomyces cerevisiae to growth in the presence of the antimitotic fungicide benomyl involves the dramatic activation of FLR1 transcription, taking place during benomyl-induced latency following sudden exposure to the fungicide. FLR1 gene encodes a plasma membrane transporter of the major facilitator superfamily (MFS) conferring resistance to multiple drugs, in particular to benomyl. FLR1 activation is completely abolished in a mutant devoided of YAP1 gene being exerted by Yap1p either directly or via Pdr3p. YAP1 gene was proved to be a determinant of benomyl resistance; the duration of the adaptation period preceding cell division under benomyl stress was longer for the Deltayap1 population, presumably due to the abolishment of FLR1 activation during latency. Although benomyl resistance mediated by Yap1p is reduced in a FLR1 deletion mutant, results also indicate that Yap1p may have other target genes that confer benomyl resistance in yeast.

Base Sequence↗
PubMed1998

Biochemical characterization of benomyl inhibition on endometrial growth during decidualization in rats.

The antimitotic action of the systemic benzimidazole carbamate compound, benomyl, the basis for its fungitoxicity, was assessed in a mammalian system by selected biochemical endpoints of endometrial proliferation during decidualization in rats. The deciduoma, artificially induced on Day 4 of pseudopregnancy (PG), represents the maternal portion of the placenta that attains maximal growth between Days 9-11 PG. Deciduoma induction by surgical uterine trauma normally prolongs PG into the decidualization process. Measured endometrial parameters were the wet weight, protein for hypertrophy, DNA indicative of hyperplasia; enzymatic biomarkers- isocitrate dehydrogenase (ICDH) and the matrix metalloproteinases (MMPs); and serum progesterone which hormonally maintains decidual growth. Benomyl was administered by oral gavage in daily doses (500 mg/kg/rat in corn oil for 5 days, PG Days 5-9) and animals were sacrificed on PG Day 10. Benomyl caused significant reduction (P < 0.001) in endometrial wet weight, protein and DNA concentrations. ICDH activity was also significantly reduced (P < 0.01) following benomyl treatment. Of the two MMP species (72 and 92 kDa), whereas the 72 kDa was only slightly affected, the 92 kDa MMP was suppressed 2-3 fold by benomyl. Benomyl was without effect on the progesterone concentration. The findings suggest that during decidualization in rats, the anti-deciduogenic, antimitotic action of post-traumal benomyl treatment which occurred via the biochemical molecules (protein, DNA, ICDH and the MMPs) apparently was not mediated by progesterone.

Animals↗
PubMed1989

A 90-day inhalation toxicity study with benomyl in rats.

Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate, CAS Registry No. 17804-35-2] is a fungicide and the possibility for inhalation exposure exists for field workers. To assess the toxicity of benomyl, groups of 20 male and 20 female CD rats were exposed nose-only 6 hr a day, 5 days a week, to concentrations of 0, 10, 50 or 200 mg/m3 of a benomyl atmosphere. At the midpoint (approximately 45 days on test) and at the end of the exposure period, blood and urine samples for clinical evaluation were collected from 10 rats/group/sex, and these animals were sacrificed for pathological examination. Similar evaluations were performed on all remaining rats at the end of the 90-day test period. After approximately 45 days on test, compound-related degeneration of the olfactory epithelium was observed in all males and in 8 of 10 female rats exposed to 200 mg/m3 benomyl. Two male rats exposed to 50 mg/m3 had similar, although less severe, areas of olfactory epithelial degeneration. After approximately 90 days of exposure, the remaining 10 rats/group/sex were sacrificed and examined. Of these rats, all of the males and females exposed to 200 mg/m3 had olfactory degeneration, along with 3 males exposed to 50 mg/m3 of benomyl. No other observed lesions were interpreted to have been caused by the benomyl exposure. In addition, male rats exposed to 200 mg/m3 benomyl had depressed mean body weights compared to controls and this finding correlated with a reduction in food consumption. Based on pathological observations, 10 mg/m3 represents the no-observable-effect level (NOEL) for the male rats, and 50 mg/m3 is the NOEL for the female rats.

Administration, Inhalation↗
PubMed1997

Protective effects of antioxidants against benomyl-induced lipid peroxidation and glutathione depletion in rats.

The present in vivo study was designed to examine the effects of the antioxidants, N,N-diphenyl-p-phenylenediamine (DPPD) and a 21-aminosteroid (U74389G), on methyl 1-(butylcarbamoyl)-2-benzimidazole-carbamate (benomyl)-induced lipid peroxidation and glutathione depletion in rats. Male Sprague Dawley rats weighing 200 250 g were used in this study and were fasted for 8 12 h before treatment. Benomyl (200 mg/kg/day in olive oil) was administered orally for 7 days to groups of untreated rats and to rats pretreated with two doses (15 mg/kg) of either DPPD or U74389G. Benomyl treatment resulted in a significant increase in serum hydroperoxides and a significant decline in hepatic reduced glutathione (GSH) levels. These results indicate that benomyl induces lipid peroxidation and glutathione depletion in rats. Benomyl-induced lipid peroxidation was blocked by DPPD pretreatment but was not significantly altered by U74389G. However, both antioxidants, DPPD and U74389G, were able to inhibit glutathione depletion induced by benomyl. The present findings indicate that the in vivo toxicity of benomyl may be associated with oxidative stress to cellular membranes and that some degree of protection against this toxicity could be afforded by antioxidants.

Animals↗
PubMed2000

An LC/MS/MS method for improved quantitation of the bound residues in the tissues of animals orally dosed with [(14)C]Benomyl.

Livers of goats orally dosed with [phenyl(U)-(14)C]benomyl contained radioactive residues which were not extractable using conventional, solvent-based extraction methods. We report a new residue method capable of enhanced extraction of benomyl-derived residues with selective and sensitive quantitation capability for methyl 4-hydroxybenzimidazol-2-ylcarbamate (4-HBC), methyl 5-hydroxybenzimidazol-2-ylcarbamate (5-HBC), and methyl benzimidazol-2-ylcarbamate (MBC). This method involves rigorous Raney-nickel reduction of hypothesized thioether bonds between benomyl residues and polar cellular components. Following acidic dehydration (desulfurization), the polar benomyl-derived residues are extracted into ethyl acetate and analyzed by LC/MS/MS. We have shown this method to be superior to alternative extraction approaches. When applied to goat liver tissue containing [phenyl(U)-(14)C]benomyl-bound residues, the extraction efficiency of total radioactive residues was approximately 30%, and the major benomyl-derived residue was 5-HBC (91-95% of extractable residue) with minor levels of carbendazim (MBC) (5-9%). HPLC/LSC data were consistent with the LC/MS/MS data. The overall method satisfies U.S. regulatory requirements in extraction efficiency, selectivity in detection, and limits of quantitation for benomyl-bound residues.

Administration, Oral↗
PubMed1995

The effects of benomyl and its breakdown products carbendazim and butyl isocyanate on the structure and function of tracheal ciliated cells.

The effects of the fungicide benomyl and its breakdown products, carbendazim and butyl isocyanate, were examined on canine tracheal epithelial tissue in primary culture. Changes in ciliary frequencies were monitored with an optical spectrum analysis system. Serial dilutions of the test compounds were prepared in 100% corn oil and applied to the cell cultures for intervals up to 6 hours and frequencies measured at intervals of 15 minutes to 1 hour. Benomyl and butyl isocyanate caused concentration-dependent decreases in ciliary beat frequency. Benomyl at 300 micrograms/ml (3 mM) caused ciliostasis within 75 minutes of exposure. Butyl isocyanate at a molar concentration three times lower than benomyl (1 mM) caused a similar response, although within 30 minutes. The IBC50 for benomyl was 0.75 mM, while for butyl isocyanate it was 0.52 mM. Carbendazim caused a moderate decrease in frequency over a 6 hour exposure period. Benomyl caused moderate to severe swelling of the mitochondria of ciliated epithelial cells with other cell organelles appearing normal. Butyl isocyanate did not cause any noticeable effect on cell ultrastructure and the apparently low rate of penetration of carbendazim into cells made it impossible to obtain an effect which justified ultrastructural analysis. It appears, at least for benomyl and butyl isocyanate, that while the physiological effect of these two compounds (inhibition of ciliary beat) is the same, the sites of action in the cell may be different.

Animals↗
PubMed1986

Effects on the fetus of maternal benomyl exposure in the protein-deprived rat.

The separate and combined effects of protein deprivation and benomyl [(methyl 1-butylcarbomoyl)-2-benzimidazole carbamate] exposure were studied in the pregnant rat fed a diet containing 24% (control) or 8% (deficient) casein throughout gestation. Within each diet group, subgroups were gavaged at 31.2 mg/kg body weight with benomyl or corn-oil carrier only on d 7-16 or 7-21 of gestation. No effects on the skeleton were seen. Benomyl exposure in the last 2 wk in dams fed the 24% casein diet resulted in a high incidence of fetal brain anomalies. This effect did not occur in those with benomyl exposure during the period of organogenesis only and was reduced in groups fed the protein-deficient diet. Exposure to benomyl in the last 2 wk in the protein-deprived rat resulted in a decrease in the weight of the fetal heart in excess of that attributable to diet alone. Lungs were a smaller portion of body weight in fetuses of benomyl-treated dams in both diet groups. The teratogenic effect on the brain in animals exposed to benomyl in wk 2 and 3 of gestation suggests that screening for teratogenic effects during organogenesis only may be insufficient.

Administration, Oral↗
PubMed1978

Mutagenicity testing of benomyl, methyl-2-benzimidazole carbamate, streptozotocin and N-methyl-N'-nitro-N-nitrosoguanidine in Salmonella typhimurium in vitro and in rodent host-mediated assays.

The fungicide benomyl and its commercial preparations Fundazol 50WP and Benlate 50WP and the benomyl metabolite methyl-2-benzimidazole carbamate and its commercial preparation MBC 50WP were tested for mutagenicity in in vitro spot tests, in microsomal plate assay, in liquid-culture treatments, or in rodent host-mediated assay. The base-pair substitution Salmonella typhimurium mutant hisG46 and the hisG46-bearing uvrB excision-repair-deficient mutants TA100, TA1530, TA1535 or TA1950 were used as test organisms. Complete genotypic information of these mutants is given in Ames et al. [2]. Captain 50WP, streptozotocin (SZN), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 2-aminopurine and N-acetylaminofluorene were used as positive control compounds. In nonoverlay spot tests Benlate 50WP was not mutagenic over a dose range of 50-5000 microgram/spot in hisG46 and TA1535. In overlay spot tests 50 or 100 microgram/spot Benomyl, MBC, Fundazol 50WP, Benlate 50WP and MBC 50WP were tested in hisG46, TA1530 or TA1950. Only a non-commercial MBC sample at 100 microgram/spot showed weak mutagenic activity in hisG46. In microsomal activation plate assay MBC, benomyl, Fundazol 50WP and Benlate 50WP were tested in TA100 over a dose range of 50-2000 microgram/plate. None of the compounds showed mutagenicity. In a 20-h liquid-culture treatment 10, 100, 1000 and 10 000 microgram/ml Fundazol 50WP were not mutagenic in TA 30. In 1-h liquid-culture treatments benomyl, Benlate 50WP or Fundazol 50WP failed to induce mutations in hisG46, TA100 or TA1950 over a dose range of 0.25-1000 microgram/ml. Appropriate positive controls were mutagenic in each experiment. The consistently negative results in this study with commercial MBC and benomyl preparations are contrary to positive results reported earlier with similar methods and similar commercial preparations. Possible reasons to explain the different results are presented. The alkylating agents SZN and MNNG induced fewer mutations in TA1530 and TA1950 uvrB excision-repair-deficient strains than in the hisG46 excision-proficient strain, indicating that with these mutagens excision-repair is also a mutation-prone process. In rodent host-mediated assays with Fundazol 50WP in mice 3 consecutive subcutaneous hourly doses of 500 mg/kg in hisG46 and TA1950 and in rats or mice an oral dose of 4000 mg/kg in TA1950 were not mutagenic. The positive control SZN was mutagenic.

Animals↗