[DNA-adduct detection in rats administered with 4,4'-methylenedianiline or 4,4'-methylenebis (2-chloroaniline)].
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Aniline Compounds↗
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Results for “Benzhydryl Compounds”
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A racephedrine-phenyltoloxamine-containing compound (Ephoxamine) in the treatment of bronchial asthma.
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Adrenergic alpha-Agonists↗
Influence of beclobrate and eniclobrate on cholesterol metabolism in rats.
Two new hypocholesterolemic compounds, ethyl-(+/-)-2-[[alpha-(p-chlorophenyl)-p-tolyl]-oxy]-2-methylbutyrate (Sgd 24 774, beclobrate) and the 3-pyridinylmethyl ester (eniclobrate), have been studied in normocholesterolemic rats. The two compounds are hepatomegalic and they lower serum and liver cholesterol levels but raise liver triglyceride levels. They also reduce the percentage of esterified cholesterol present in the serum. Beclobrate enhances hepatic HMG-CoA reductase activity but does not affect cholesterol-7 alpha hydroxylase. Eniclobrate, on the other hand, increases activity of the hydroxylase but not of HMG-CoA reductase. Neither compound affects cholesterol absorption.
Animals↗
Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs.
The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.
Amphetamine↗
Further evidence for a biological role of anti-estrogen-binding sites in mediating the growth inhibitory action of diphenylmethane derivatives.
Several diphenylmethane derivatives have been synthesized with variable affinities for Anti-estrogen Binding Sites (ABS) but not for the estrogen receptor. Using these molecules as probes it is shown that their binding affinities for ABS correlate with their abilities to inhibit the growth of MCF-7 human breast cancer cells. In contrast they have no influence on the proliferation of tamoxifen-resistant variant cells (RTx6) in which ABS are undetectable. These data support the conclusion that ABS has a functional role in the anti-proliferative effect of triphenylethylene anti-estrogens and structurally related compounds.
Benzhydryl Compounds↗
Stimulation of calbindin-D(9k) mRNA expression in the rat uterus by octyl-phenol, nonylphenol and bisphenol.
Quantification of estrogen-induced changes in the expression levels of endogenous genes such as pS2 and vitellogenin could be an assay to detect estrogenicity of chemicals. Considering its regulation by estrogen, in the present study, we hypothesize that the calbindin-D(9k) (CaBP-9k) gene has the possibility as a biomarker for estrogenic response of the environmental estrogens. We analyzed the time- and dose-dependent CaBP-9k mRNA expression in the immature rats by 3-day injection of 17beta-estradiol (E2) and alkylphenol acid [octyl-phenol (OP) and nonylphenol (NP)] and bisphenol A(BPA)) which are environmentally persistent and reported to have some estrogenic activity in experimental test systems. The expression of CaBP-9k mRNA was compared with uterotropic response of the compounds. A significant increase in CaBP-9k mRNA expression was observed when treated with 1000 mg/kg body weight (BW) per day of OP (18-fold versus control), NP (17-fold versus control) and BPA (6-fold versus control) for 3 days in dot blot assays. Using Northern blot analysis, a more dramatic increase of CaBP-9k mRNA expression was observed when treated with 1000 mg/kg BW per day of OP (132-fold versus control) and NP (113-fold versus control) for 3 days. Treatment with 10 and 100 mg/kg BW per day of NP and 100 mg/kg BW per day of OP for 3 days induced a small but significant increase in CaBP-9k mRNA expression. As expected, a single dose of E2 (40 microg/kg BW per day) for 3 days induced a significant increase in CaBP-9k mRNA expression as revealed by dot (15-fold versus control) or Northern blot assay (102-fold versus control). In a time response experiment using Northern blot assay, a significant increase in CaBP-9k mRNA expression was observed as early as 3 h, peaked at 6 h and continued until 72 h after treatment with 1000 mg/kg BW per day of OP, NP, and 48 h after treatment with 1000 mg/kg BW per day of BPA. A similar time-dependent response was observed when assessed by dot blot assay. Uterotropic response of the compounds was determined and compared with CaBP-9k mRNA expression. The alkylphenolic compounds induced a significant increase in the uterine wet weight at 1000 mg/kg BW per day of OP and NP, not BPA. A strong correlation between in vivo uterotropic assay and CaBP-9k mRNA expression assay was observed. In order to investigate the possible mechanisms by which the compounds regulate CaBP-9k mRNA expression, we studied the effect of the compound on the ERalpha mRNA level using total RNA from the treated rats. The alkylphenolic compounds as well as E2 stimulate the expression of ERalpha mRNA in a similar pattern to that of CaBP-9k mRNA in terms of dose- and time-dependent response. Strong regulation of CaBP-9k mRNA expression by E2 and the environmental estrogens and its correlation with in vivo uterotropic assay suggest that CaBP-9k gene can be used as a biomarker gene for assaying estrogenicity of putative estrogenic compounds.
Animals↗
Quantitative detection of bisphenol A and bisphenol A diglycidyl ether metabolites in human plasma by liquid chromatography-electrospray mass spectrometry.
Due to the ubiquity of epoxy resin compounds and their potential role in increasing the risk for reproductive dysfunction and cancer, the need for an assessment of human exposure is urgent. Therefore, we developed a method for measuring bisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE) metabolites in human blood samples using high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-MS). Human blood samples were processed using enzymatic deconjugation of the glucuronides followed by a novel sample preparation procedure using a solid-phase-cartridge column. This selective analytical method permits rapid detection of the metabolites, free BPA and a hydrolysis product of BADGE (BADGE-40H) with detection limits in the low nanogram per milliliter range (0.1 ng ml(-1) of BPA and 0.5 ng ml(-1) of BADGE-40H). The sample extraction was achieved by Oasis HLB column on gradient elution. The recoveries of BPA and BADGE-40H added to human plasma samples were above 70.0% with a standard deviation of less than 5.0%. This selective, sensitive and accurate method will assist in elucidating potential associations between human exposure to epoxy-based compounds and adverse health effects.
Benzhydryl Compounds↗
Effect of heat processing and storage time on migration of bisphenol A (BPA) and bisphenol A-diglycidyl ether (BADGE) to aqueous food simulant from Mexican can coatings.
Effects of heat processing and storage time (up to 70 days) on migration of bisphenol A (BPA) and bisphenol A-diglycidyl ether (BADGE) from can coatings into an aqueous food simulant were determined. Distilled water was canned in two types of Mexican cans: for tuna and for jalapeño peppers. Results showed that there is an effect of heat treatment on migration of both compounds. Storage time did not show any effect in BPA migration from tuna cans. There was an effect of storage time on BPA migration from jalapeño pepper cans. Results for BADGE migration were affected by its susceptibility to hydrolyze in aqueous simulants. BADGE concentration decreased, or was not detected, during storage in both types of cans. Migration levels for BPA and BADGE were within 0.6-83.4 and <0.25-4.3 microg/kg, respectively. Both were below European and Mercosur legislation limits. Other migrating compounds were detected, although no identification was performed.
Benzhydryl Compounds↗
Estrogen-like properties of brominated analogs of bisphenol A in the MCF-7 human breast cancer cell line.
Tetrabromobisphenol A (TeBBPA) is a four-meta-brominated variant of bisphenol A (BPA) and is one of the most commonly used brominated flame retardants worldwide. We compared the estrogenic potency of TeBBPA, BPA and the brominated analogs mono- (MBBPA), di- (DBBPA), and tribromobisphenol A (TrBBPA) in the estrogen-dependent human breast cancer cell line MCF-7. All of the compounds competed with 17beta-estradiol for binding to the estrogen receptor, although the affinity of the test chemicals to the estrogen receptor was much lower than that of 17beta-estradiol. TrBBPA and TeBBPA showed a considerably lower access to the estrogen receptors within intact MCF-7 cells incubated in 100% serum compared to incubation in serum-free medium, indicating a strong binding to serum proteins. BPA, MBBPA, and DBBPA showed only a slightly reduced access to the receptors. All of the test compounds induced proliferation in MCF-7 cells, the potential decreasing with increasing number of bromo-substitutions. TeBBPA did not induce maximal cell growth, indicating cytotoxic effects at high concentrations. BPA and the brominated analogs, except TeBBPA, induced progesterone receptor and pS2 to the same extent as 17beta-estradiol, although at much higher concentrations. Our studies demonstrate that compared to 17beta-estradiol, BPA and the brominated analogs have much lower estrogenic potencies for all of the endpoints tested, TeBBPA being the least estrogenic compound.
Benzhydryl Compounds↗
Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor.
By using a yeast detection system for androgenic and antiandrogenic effects of chemicals, we identified bisphenol A (BPA) and nonylphenol (NP) as antiandrogens. In this study, we report molecular mechanisms for the antiandrogenic action of BPA and NP. In the ARhLBD-activating signal cointegrator 1 (ASC1) yeast two-hybrid system, which reflects the androgen-dependent interaction between androgen receptor (AR) and its coactivator, ASC1, BPA and NP acted as potent AR antagonists comparable to a known strong antagonist, cyproterone acetate. Ligand competition assays revealed that [3H]5alpha-dihydroxytestosterone (DHT) binding to AR is inhibited a maximum of 30 and 40% at approximately 5 nM of NP and 50 nM of BPA, respectively. In addition, the nuclear translocation of green fluorescent protein (GFP)-AR fusion protein in the presence of testosterone was affected by the addition of BPA and NP, which cause rather dispersed distribution of GFP-AR between the nuclear and the cytoplasmic compartments. Furthermore, in transient transfection assays, BPA and NP inhibited androgen-induced AR transcriptional activity. Taken together, the results suggest that BPA and NP affect multiple steps of the activation and function of AR, thereby inhibiting the binding of native androgens to AR, AR nuclear localization, AR interaction with its coregulator, and its subsequent transactivation. These data may help us better understand the biological alterations induced by these environmental compounds.
Androgen Antagonists↗
Differential effects of the new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behaviour in elderlies.
Modafinil (CRL 40476) is a new central alpha-adrenergic agonist with vigilance-promoting properties. In a double-blind, placebo-controlled sleep laboratory study its single-dose effects on sleep and early morning behaviour were investigated and compared with d-amphetamine. Ten elderly healthy volunteers (mean age: 68 years) spent 12 nights in the sleep laboratory: one adaptation night, one baseline night, five drug nights (100 mg and 200 mg modafinil; 10 mg and 20 mg d-amphetamine; placebo) and five subsequent washout nights. The drugs were administered orally in one week intervals at 10:00 p.m., and all-night somnopolygraphic investigations were performed between 10:30 p.m. and 6:00 a.m. A self-rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. d-amphetamine caused a dose-dependent impairment of sleep maintenance and sleep architecture, while modafinil did not. Thus, a significant reduction of total sleep time, REM-sleep and sleep stage 2 was seen after d-amphetamine when compared to placebo and 100 mg modafinil. Corresponding with these objective results, subjective sleep quality deteriorated significantly only after 20 mg d-amphetamine as compared to placebo. Morning investigations revealed an increase of CFF after 20 mg d-amphetamine. Pulse rate, evening and morning blood pressure remained unchanged. These findings suggest a different mode of action of the two compounds.
Aged↗
[Inhibition of non-cytotoxic histamine liberation from isolated rat mast cells by antihistaminic preparations].
Phenothiazines (chlorpromazine and promethazine) and antihistaminic quinuclidine derivatives [phencarol, quinuclidyl-3-di-(o-tolyl) carbinol, hydrochloride quinuclidyl-3-di-(o-methoxyphenyl) carbinol--HQMC] at concentrations preceding the histamine-releasing ones inhibited the compound 48/80-induced histamine release from the isolated rat mast cells. HQMC inhibited histamine release induced by selective liberators (compound 48/80, MCD-peptide, specific antigen), but potentiated histamine release induced by nonselective liberators (chlorpromazine, tryton X-100). The inhibition by HQMC of histamine release induced by compound 48/80 increased during 1 min and was reversible. The inhibitory effect of all the compounds tested was partially counteracted by glucose.
Animals↗
Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials.
4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time.
Aniline Compounds↗
Methylene dianiline: assessment of exposure and cancer morbidity in power generator workers.
The biaromatic amine 4,4'-methylene dianiline (MDA) is an animal carcinogen, possibly also carcinogenic to humans. In a cohort of 595 power generator workers potentially exposed to MDA in a curing agent of an epoxy system, the overall standardised cancer incidence ratio (SIR) among males (n = 550), however, was only 0.52 [95% confidence interval (CI) 0.16-1.21] based on five observed cases. One male urinary bladder cancer case was found in comparison to 0.6 expected (SIR 1.67; 95% CI 0.04-9.31). This case was identified in an unexposed subcohort. High levels of MDA metabolites were ascertained in the urine of currently exposed workers, probably following percutaneous absorption. Although no evidence of an increased overall or bladder cancer risk was detected, the limitations of the study in regard to the size of the cohort, age and cancer latency preclude a definite risk assessment. The dermal absorption of MDA has been highlighted.
Aniline Compounds↗
Disposition and metabolism of the carcinogen reduced Michler's ketone in rats.
Studies on the in vivo and in vitro disposition of 4,4'-[14C]-methylenebis(N,N-dimethyl)benzamine (reduced Michler's ketone, RMK) were performed. Osborne-Mendel rats retained, after 24 hr, 78% of a p.o. dose of [14C]RMK. At 24 hr after an i.p. dose, fat, liver, and intestine represented major sites for deposition of radioactivity. The major urinary metabolite of RMK, representing 36% of the total radioactivity recovered in the urine, was N,N'-diacetyl-4,4'-(hydroxymethylene)dianiline. In vitro microsomal metabolism of RMK involved demethylation. Products included N,N-dimethyl-4,4'-methylenedianiline, N,N'-dimethyl-4,4'-methylenedianiline, N-methyl-4,4'-methylenedianiline, and 4,4'-methylenedianiline, representing 44.7, 5.3, 11.8, and 6.9%, respectively, of the total radioactivity recovered from the reaction mixture. Although none of the microsomal metabolites was a direct-acting mutagen in the standard Salmonella typhimurium assay, all could be activated to mutagens when incubated with 9000 X g liver supernatants and reduced nicotinamide adenine dinucleotide phosphate. The activation of 4,4'-methylenedianiline to a mutagen suggests that the methyl groups of RMK are not required for the conversion of RMK to a reactive electrophile.
Adipose Tissue↗
[Synthesis of heterocyclic compounds by condensation of 5-chloro-2-amino-benzhydrylamine with C1 - C2 - reagents (author's transl)].
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Benzhydryl Compounds↗
Impact of reaction conditions on the laccase-catalyzed conversion of bisphenol A.
The oxidative conversion of aqueous BPA catalyzed by laccase from Trametes versicolor was conducted in a closed, temperature-controlled system containing buffer for pH control. The effects of medium pH, buffer concentration, temperature and mediators and the impacts of dissolved wastewater constituents on BPA conversion were investigated. The optimal pH for BPA conversion was approximately 5, with greater than half maximal conversion and good enzyme stability in the range of 4-7. The stability of the enzyme was not impacted by buffer concentration, nor was BPA conversion. Despite the observation that the enzyme tended to be inactivated at elevated temperatures, enhanced conversion of BPA was observed up until a reaction temperature of 45 degrees C. Of the mediators studied, ABTS was most successful at enhancing the conversion of BPA. Dissolved wastewater constituents that were studied included various inorganic salts, organic compounds and heavy metal ions. BPA conversion was inhibited in the presence of anions such as sulfite, thiosulfate, sulfide, nitrite and cyanide. The metal ions Fe(III) and Cu(II) and the halogens chloride and fluoride substantially suppressed BPA conversion, but the presence of selected organic compounds did not significantly reduce the conversion of BPA.
Anions↗
Relationships between the abnormalities of the male reproductive organs and the accumulation of phenol compounds in the striped field mouse, Apodemus agrarius, inhabiting Korea.
The relationships between the abnormalities of the male reproductive organs in striped field mice and the accumulation of endocrine-disrupting chemicals were assessed. Most mice collected at three areas were contaminated with phenol or organotin compounds. Fourteen to 42% of the mice at each area had abnormally shrunken reproductive organs, and some of them were contaminated with high levels of phenol compounds. Moreover, all the shrunken reproductive organs were damaged in the histological structure. The damage was observed also from several mice accumulating a high level of phenol compounds even though they had normally developed reproductive organs, although no damage was found in the mice accumulating a high level of organotin compounds. Collectively, the abnormalities of the reproductive organs in the mice seemed to be related to the accumulation of phenol compounds rather than of organotin compounds.
Animals↗