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PubMed2006

A characterization of selected endocrine disruptor compounds in a Portuguese wastewater treatment plant.

Anthropogenic compounds that are able to disrupt the endocrine system of wildlife species are a major cause for concern and have led to a demand for new screening methods. The identification and quantification of endocrine disruptor compounds at wastewater treatment plant is of major interest to assess the endocrine activity of wastewater treatment plant discharges into the environment. This study consists of a preliminary survey of concentrations of previously selected endocrine disruptor compounds, undertaken to establish environmental concentrations and to support a biological program assay exposing freshwater fish to them. Selected endocrine disrupting chemicals (APEs, bisphenol A and 17 beta-estradiol) were measured in samples from a wastewater treatment plant located in Lisbon (Portugal), using recent commercial enzyme-linked immunosorbent assay kits and also LC-MS/MS. The results show that the wastewater treatment plant treatment process is efficient on the removal of target endocrine disruptor compounds. However, environmentally significant concentrations are still present in the treated effluent. The results also show that enzyme-linked immunosorbent assay kit is suitable for routine analysis of the selected compounds. The results are also useful since the wastewater treatment plant is located in a Mediterranean region, which results in an effluent with its own characteristics.

Benzhydryl Compounds↗

PubMed2006

Determination of endocrine-disrupting compounds in cereals by pressurized liquid extraction and liquid chromatography-mass spectrometry. Study of background contamination.

A sensitive method based on pressurized liquid extraction (PLE) and liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) has been developed for the determination in cereal samples of seven endocrine-disrupting compounds: bisphenol A (BPA), 4-tert-butylbenzoic acid (BBA), 4-nonylphenol (NP), 4-tert-butylphenol (t-BP), 2,4-dichlorophenol (DCP), 2,4,5-trichlorophenol (TCP) and pentachlorophenol (PCP). For the PLE procedure, methanol was selected as the extraction solvent. An experimental design approach was applied to optimize other PLE parameters. The recoveries achieved for the all seven compounds were in the 81-104% range, with relative standard deviations of 4-9%. An additional preconcentration step, based on solid-phase extraction (SPE), after the PLE step proved to be a successful way for obtaining a more sensitive method. The detection limits achieved in corn breakfast cereals were in the 0.003-0.013 microg g(-1) range, except for BPA, with a detection limit of 0.043 microg g(-1), for a sample size of 2.5 g. These values are similar to or even lower than currently legislated limits for pesticides in cereals and cereal-based foodstuffs. We also investigated possible contamination during the experimental process by the target compounds released from purified water, plastics, syringes, peristaltic pump tubes, glassware and other laboratory materials in contact with the samples along the analytical process.

Analytic Sample Preparation Methods↗

PubMed2006

An observational study of the potential exposures of preschool children to pentachlorophenol, bisphenol-A, and nonylphenol at home and daycare.

The Children's Total Exposure to Persistent Pesticides and Other Persistent Organic Pollutants (CTEPP) study investigated the potential exposures of 257 preschool children, ages 1 1/2-5 yr, and their primary adult caregivers to more than 50 anthropogenic chemicals. Field sampling took place in selected counties in North Carolina (NC) and Ohio (OH) in 2000-2001. Over a 48-h period in each child's daycare center and/or home, food, beverages, indoor air, outdoor air, house dust, soil, participants' hand surfaces and urine were sampled. Additional samples-transferable residues, food preparation surface wipes, and hard floor surface wipes-were collected in the approximately 13% of the homes that had pesticide applications within the 7 days prior to field sampling. Three phenols were among the measured chemicals: pentachlorophenol (PCP), bisphenol-A [2,2-bis(4-hydroxyphenyl)propane], and nonylphenol (4-n-nonylphenol). Nonylphenol (NP) was detected in less than 11% of the samples in any medium. Among samples that were collected at all participants' homes and daycare centers, PCP was detected in >50% of indoor air, outdoor air, house dust, and urine samples; bisphenol-A (BPA) was detected in >50% of indoor air, hand wipe, solid food, and liquid food samples. The concentrations of the phenols in the sampled media were measured, and the children's potential exposures and potential absorbed doses resulting from intake through the inhalation, dietary ingestion, and indirect ingestion routes of exposure were estimated. The children's potential exposures to PCP were predominantly through inhalation: 78% in NC and 90% in OH. In contrast, their potential exposures to BPA were predominantly through dietary ingestion: 99%, for children in both states. The children's estimated exposures to PCP, calculated from the amounts excreted in their urine, exceeded their estimated maximum potential intake, calculated from the multimedia PCP concentrations, by a factor greater than 10. This inconsistency for PCP highlights the need for further research on the environmental pathways and routes of PCP exposure, investigation of possible exposures to other compounds that could be metabolized to PCP, and on the human absorption, metabolism, and excretion of this phenol over time periods longer than 48 h.

Benzhydryl Compounds↗

PubMed2005

Evaluation of liver and peripheral blood micronucleus assays with 9 chemicals using young rats. A study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study Group (MMS).

We conducted simultaneous liver and peripheral blood micronucleus assays in young rats with seven rodent hepatocarcinogens-4,4'-methylenedianiline (MDA), quinoline, o-toluidine, 4-chloro-o-phenylenediamine (CPDA), dimethylnitrosamine (DMN), p-dimethylaminoazobenzene (DAB), and di(2-ethylhexyl)phthalate (DEHP)-and two mutagenic chemicals-kojic acid and methylmethanesulfonate (MMS). Quinoline, DMN, and DAB were positive in the liver assay, while o-toluidine, kojic acid, DAB, and MMS were positive in the peripheral blood assay. o-Toluidine, kojic acid, and DAB are reportedly negative in mouse bone marrow micronucleus assays, indicating a species difference. Our results revealed a correlation between micronucleus induction in hepatocytes and hepatocarcinogenicity. This technique can be useful for the detection of micronucleus-inducing chemicals that require metabolic activation, and it enables simultaneous comparison of the micronucleus-inducing potential of chemicals in the liver and peripheral blood in the same individual.

Aniline Compounds↗

PubMed2006

Pharmacogenetic tools for the development of target-oriented cognitive-enhancing drugs.

The identification of the anatomical and physiological substrates involved in the regulation of the dorsolateral prefrontal cortex function in humans provided the basis for the understanding of mechanisms involved in cognitive and executive function under normal as well as pathological conditions. In this context, substantial evidence indicates that alterations in monaminergic function in the dorsolateral prefrontal cortex significantly contributes to the cognitive impairments present in schizophrenia, attention deficit disorders, and other neuropsychiatric conditions. The development of a number of compounds that selectively increase extracellular dopamine (DA) concentrations in the dorsolateral prefrontal cortex but not in subcortical areas by either blocking its metabolism or reuptake, or increasing its release, or that directly activate postsynaptic DA-1 receptor mechanisms provided powerful pharmacotherapeutic tools to mitigate the cognitive deficits brought about by the dopaminergic alterations of the prefrontal cortex. More recently, the findings that polymorphisms of the catecholamine-O-methyl-transferase gene may also modify the effect of these drugs on the prefrontal cortex points toward a more specific genotype-based neuropsychopharmacology for the treatment of cognitive deficits in schizophrenia as well as in a number of other neuropsychiatric conditions. The ability of these compounds to increase DA load selectively in the frontal cortex and not on subcortical systems allows a targeted intervention without the stimulant-like effects observed with older drugs used to treat those conditions.

Benzhydryl Compounds↗

PubMed2003

The biomarker and endocrine disruptors in mammals.

The compounds that bind steroid hormone receptors including estrogen receptors (ERs), progesterone receptor (PR) or androgen receptor (AR), and induce or modulate a steroid hormone receptor-mediated response could be defined as endocrine disruptors (EDs). Currently, there are no standard methods to determine whether a chemical is an endocrine disruptor or not. Most results of in vitro and in vivo data are derived from assays that measure estrogenic activity, thus fewer data are available from assays that measure androgenic and progestogenic activities. In this review, we introduce a novel in vivo model to detect EDs using immature rats in the induction of Calbindin-D(9k) (CaBP-9k) mRNA and protein by estrogenic compounds. In addition, we summarize other biomarkers and screening methods for EDs in mammals to describe the usefulness of indicated biomarkers, although mammalian models are very few based on experimental findings.

Animals↗

PubMed1984

Neoplastic response of F344 rats and B6C3F1 mice to the polymer and dyestuff intermediates 4,4'-methylenebis(N,N-dimethyl)-benzenamine, 4,4'-oxydianiline, and 4,4'-methylenedianiline.

Feeding 4,4'-methylenebis(N,N-dimethyl)benzenamine [CAS: 101-61-1; 4,4'-methylenebis(N,N-dimethylaniline)] to inbred F344 rats increased the incidence of thyroid lesions (hyperplasia, adenomas, and carcinomas) in both sexes, especially in the female rats. 4,4'- Oxydianiline (CAS: 101-80-4) in the diet increased adenomas and carcinomas in the thyroid gland and neoplastic nodules and carcinomas in the liver of male and female F344 rats. In addition to increasing thyroid adenomas in females and hepatocellular adenomas or carcinomas in male and female B6C3F1 mice, 4,4'- oxydianiline increased adenomas of the harderian gland in male and female mice. 4,4'- Methylenedianiline (CAS: 101-77-9) in the drinking water increased neoplasms of the thyroid gland and liver in F344 rats and B6C3F1 mice.

Aniline Compounds↗

PubMed1985

The metabolic activation of 4,4'-methylene-bis-(2-chlorobenzeneamine) to a bacterial mutagen by hepatic postmitochondrial supernatant from human and other species.

4,4'-Methylene-bis-(2-chlorobenzeneamine) (MbOCA) is a commercially important industrial chemical that is carcinogenic in three animal species and mutagenic in the Ames test. The ability of hepatic postmitochondrial supernatant from humans, dogs, mice, and rats to activate MbOCA to a bacterial mutagen has been investigated using the Ames plate incorporation test and a bacterial fluctuation test. In the Ames plate test, hepatic S9 preparations from mice and Aroclor 1254-induced rats only were sufficiently active to produce a significant mutagenic response. Preincubation of MbOCA with S9 from human liver produced a slight increase in the number of revertants but not a doubling as compared to controls. However, using the more sensitive bacterial fluctuation test, liver S9 from all species activated MbOCA to a bacterial mutagen. The responses produced were dose-related and, for at least part of the dose range, were double the background levels observed in controls. The increases in the mutagenicity of MbOCA produced by liver S9 from humans, dogs, and rats were significant at the 0.1% level of probability. Liver S9 preparations from all species in which MbOCA is carcinogenic have now been demonstrated to be capable of activating this compound to a bacterial mutagen. The finding that S9 from human liver can also activate MbOCA to a mutagen increases the concern that it may be a human carcinogen.

Animals↗

PubMed2002

Determination of bisphenol-type contaminants from food packaging materials in aqueous foods by solid-phase microextraction-high-performance liquid chromatography.

A fast screening method consisting of off-line solid-phase microextraction coupled to HPLC and fluorescence detection, suitable for the analysis of several bisphenol derivatives and their degradation products in aqueous solution, has been developed. Detection limits of 0.7 ng ml(-1) for 2,2-bis[4-(glycidyloxy)phenyl]propane, 0.9 ng ml(-1) for bisphenol A bis(3-chloro-2-hydroxypropyl)ether, 1.1 ng ml(-1) for 2,2-bis(4-hydroxyphenyl)propane and 2.4 ng ml(-1) for bisphenol F diglycidyl ether have been achieved working in the linear range 10-500 ng ml(-1). The good analytical features achieved make the proposed method an interesting option for the direct determination of these compounds in aqueous canned food such as peas, tuna, olives, maize, artichokes or palm hearts. Both the optimization process and the results, including the analysis of real samples, are given and discussed.

Benzhydryl Compounds↗

PubMed2005

Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats.

The Organization for Economic Cooperation and Development (OECD) is developing a screening and testing method to identify estrogenic/antiestrogenic compounds. Based on these demands, phase 1 study for OECD uterotrophic assay was undertaken. The OECD is in the process of validating the assay results from international participating laboratories, which carried out this study with established environmental estrogenic compounds using designed protocols. The aim of this study was to provide data for validating the OECD uterotrophic assay using Sprague-Dawley immature female rats when testing with weak or partial estrogenic compounds. Ethinyl estradiol (EE) at 0.3 or 1 microg/kg/d, a positive control used in the present study, significantly increased both uterine wet and blotted weights. In the case of weak estrogenic compounds, the uterine wet weights were significantly increased by bisphenol A (BPA) at 300 mg/kg/d, nonylphenol (NP) at 80 mg/kg/d, genistein (GN) at 35 mg/kg/d, and methoxychlor (MXC) at 500 mg/kg/d. In addition, the increase in uterine blotted weights also showed a similar pattern to that of uterine wet weights. However, both 1,1,1-trichloro-2,2-bis(p-chlorphenyl)ethane (o,p-DDT) and dibutyl phthalate (DBP) did not affect uterus (wet and blotted) weights at doses of 100 and 500 mg/kg/d. These results suggest that the increase in uterine weights should be considered useful as a sensitive endpoint for detecting weak estrogenic compounds in 3-d rodent uterotrophic assay. However, further combination studies using surrogate biomarkers may be needed to improve the sensitivity of this assay for the detection of weak estrogenic compounds, such as o,p-DDT.

Animals↗

PubMed2000

Anaerobic-aerobic process for microbial degradation of tetrabromobisphenol A.

Tetrabromobisphenol A (TBBPA) is a flame retardant that is used as an additive during manufacturing of plastic polymers and electronic circuit boards. Little is known about the fate of this compound in the environment. In the current study we investigated biodegradation of TBBPA, as well as 2,4,6-tribromophenol (TBP), in slurry of anaerobic sediment from a wet ephemeral desert stream bed contaminated with chemical industry waste. Anaerobic incubation of the sediment with TBBPA and peptone-tryptone-glucose-yeast extract medium resulted in a 80% decrease in the TBBPA concentration and accumulation of a single metabolite. This metabolite was identified by gas chromatography-mass spectrometry (GC-MS) as nonbrominated bisphenol A (BPA). On the other hand, TBP was reductively dehalogenated to phenol, which was further metabolized under anaerobic conditions. BPA persisted in the anaerobic slurry but was degraded aerobically. A gram-negative bacterium (strain WH1) was isolated from the contaminated soil, and under aerobic conditions this organism could use BPA as a sole carbon and energy source. During degradation of BPA two metabolites were detected in the culture medium, and these metabolites were identified by GC-MS and high-performance liquid chromatography as 4-hydroxybenzoic acid and 4-hydroxyacetophenone. Both of those compounds were utilized by WH1 as carbon and energy sources. Our findings demonstrate that it may be possible to use a sequential anaerobic-aerobic process to completely degrade TBBPA in contaminated soils.

Aerobiosis↗

PubMed2007

Biodegradation of bisphenol A and related compounds by Sphingomonas sp. strain BP-7 isolated from seawater.

A bacterium capable of assimilating 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), strain BP-7, was isolated from offshore seawater samples on a medium containing bisphenol A as sole source of carbon and energy, and identified as Sphingomonas sp. strain BP-7. Other strains, Pseudomonas sp. strain BP-14, Pseudomonas sp. strain BP-15, and strain no. 24A, were also isolated from bisphenol A-enrichment culture of the seawater. These strains did not degrade bisphenol A, but accelerated the degradation of bisphenol A by Sphingomonas sp. strain BP-7. A mixed culture of Sphingomonas sp. strain BP-7 and Pseudomonas sp. strain BP-14 showed complete degradation of 100 ppm bisphenol A within 7 d in SSB-YE medium, while Sphingomonas sp. strain BP-7 alone took about 40 d for complete consumption of bisphenol A accompanied by accumulation of 4-hydroxyacetophenone. On a nutritional supplementary medium, Sphingomonas sp. strain BP-7 completely degraded bisphenol A and 4-hydroxyacetophenone within 20 h. The strain degraded a variety of bisphenols, such as 1,1-bis(4-hydroxyphenyl)ethane, 2,2-bis(4-hydroxy-3-methylphenyl)propane, 2,2-bis(4-hydroxyphenyl)butane, and 1,1-bis(4-hydroxyphenyl)cyclohexane, and hydroxy aromatic compounds such as 4-hydroxyacetophenone, 4-hydroxybenzoic acid, catechol, protocatechuic acid, and hydroquinone. The strain did not degrade bis(4-hydroxyphenyl)methane, bis(4-hydroxyphenyl)sulfone, or bis(4-hydroxyphenyl)sulfide.

Benzhydryl Compounds↗

PubMed1992

[A case of hypersensitivity pneumonitis in which serum specific antibodies for three species of isocyanate molecules were demonstrated].

A 64-year-old male was admitted to our hospital with complaints of the development of high fever, cough and dyspnea 5-6 hours after painting automobiles. His chest X-ray film showed interstitial shadows in both lungs. Pulmonary function test demonstrated reduction of diffusion capacity; and blood gas analysis demonstrated hypoxemia and an increase in alveolar-arterial oxygen tension difference. Marked lymphocytosis and a striking decrease in CD4/CD8 ratio were observed in the bronchoalveolar lavage fluid. Transbronchial lung biopsy specimens showed alveolitis and Masson's bodies. We suspected that the patient was suffering from hypersensitivity pneumonitis induced by isocyanates contained in the urethane paint he used. Immunological studies were performed using chemical compounds of three species of isocyanate molecules (TDI, MDI, HDI) and human serum albumin (HSA). The results were as follows: skin tests were positive for TDI-HSA and MDI-HSA; lymphocyte-stimulation tests on peripheral blood were positive for TDI-HSA; precipitation reaction was negative for all the isocyanates studies; enzyme-linked immunosorbent assay (ELISA) demonstrated the existence of specific IgG antibodies for TDI, MDI and HDI; inhalation challenge test by TDI-HSA was negative, but environmental provocation was considered to be positive. We diagnosed his pulmonary disorder as hypersensitivity pneumonitis due to isocyanates. Type III and Type IV allergic reactions of Gell-Coombs were suggested to be involved in the pathogenesis, however, there remains the possibility that the instability of isocyanate compounds as antigen modified the results of our immunological studies.

Alveolitis, Extrinsic Allergic↗

PubMed2004

Bisphenol A: a scientific evaluation.

Bisphenol A (BPA) is used in the production of high-volume polycarbonate and epoxy resin compounds found in a number of consumer products, including plastic bottles and the linings of canned goods. As a result of such applications, very small amounts of BPA can migrate into food and drink. In light of reports suggesting that low doses of BPA cause estrogenic effects in laboratory animals, concerns were raised about the safety of these consumer products, particularly plastic bottles used for feeding milk to babies. To evaluate the risk, if any, from BPA, investigations were undertaken to more precisely determine human exposure levels and more carefully study the validity of the low-dose effects reported. On the basis of the most realistic studies of BPA levels in food and drink, as well as in human urine, it has been estimated that human exposures, including those of children, are very low and range from about .001 to .1 mcg/kg body weight (bw)/day. The results of the additional toxicology studies indicated that the low-dose effects could not be consistently replicated. In light of this, a number of governments and agencies brought together independent expert panels to carefully evaluate the toxicologic studies and provide regulatory guidance. These panels came to a similar conclusion, namely, that low-dose effects have not been demonstrated. They also supported the acceptable daily intake levels previously calculated on the basis of high-dose effects shown in laboratory animals. Comparing these acceptable intakes with the best exposure estimates reveals that human doses of BPA from migration of the compound into food and drink are orders of magnitude lower than acceptable daily intakes. Thus, it is very unlikely that humans, including infants and young children, are at risk from the presence of BPA in consumer products.

Animals↗

PubMed1999

In vitro vitellogenin production by carp (Cyprinus carpio) hepatocytes as a screening method for determining (anti)estrogenic activity of xenobiotics.

The yolk protein precursor vitellogenin (Vtg) is secreted by the liver of female as well as male fish, in response to estrogenic compounds. In this study, an in vitro assay was developed for measuring Vtg induction, using cultured primary hepatocytes from genetically uniform strains of carp (Cyprinus carpio). Vtg production was measured by indirect competitive ELISA, using a polyclonal antiserum against goldfish Vtg that cross-reacts with carp Vtg. Vtg was dose-dependently induced by 17beta-estradiol (E2) in hepatocytes of both sexes. E2 had a lowest observed effect concentration (LOEC) for Vtg induction of 2 nM, an EC50 between 50 and 150 nM, and a maximum response at 2 microM. The plasticizer and xenoestrogen bisphenol-A induced Vtg secretion by hepatocytes of both sexes at 50 and 100 microM. This carp hepatocyte (CARP-HEP) assay can also be used to detect antiestrogenic activity, which was measured as the reduction of E2-stimulated Vtg synthesis. Two well-known antiestrogenic compounds, tamoxifen and 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), were tested. TCDD caused a reduction in Vtg synthesis in female hepatocytes at concentrations <0.1 nM, making it approximately 10,000-fold more potent than tamoxifen. Carp hepatocytes were also sensitive to induction of cytochrome P4501A (CYP1A) activity, measured as ethoxyresorufin O-deethylase (EROD). Depending on the exposure time, 18 or 96 h, EROD EC50 values for TCDD were 27 or 6 pM, respectively. The CARP-HEP assay, using the 96-well plate format, offers good possibilities to screen large numbers of compounds for (anti)estrogenic properties. In addition, it can simultaneously determine aryl hydrocarbon receptor agonist properties, measured as CYP1A induction.

Animals↗

PubMed2002

Effects of bisphenol a on the reproduction of Japanese medaka (Oryzias latipes).

We elucidated the effects of bisphenol A (BPA) on the reproductive capacity (fecundity and fertility) and estrogenic response of adult Japanese medaka (Oryzias latipes) and studied the transgenerational effects (F, generation growth and sex) of this agent on the F1 offspring. Eight mating pairs of medaka were exposed to BPA for three weeks at a measured concentration of 837, 1,720, or 3,120 microg/L. Throughout the exposure period, we observed no reduction of fecundity and fertility in any treatment group and no reduction in survival and growth or any imbalance of the sex ratio of the offspring. However, histologic examination revealed testis-ova in 13% of the males in the 837-microg/L treatment group, 86% of those in the 1,720-microg/L group, and 50% of those that received 3,120 microg BPA/L. In addition, concentrations of hepatic vitellogenin were increased significantly in males treated with BPA at 3,120 microg/L (p = 0.0148). These results suggest that BPA is a weakly estrogenic compound that has the potential to alter sexual development and induce vitellogenin in male medaka but that has no adverse effect on reproductive success.

Animals↗

PubMed2006

Effects of methylenedianiline on tight junction permeability of biliary epithelial cells in vivo and in vitro.

Methylenedianiline (DAPM) is considered a cholangiodestructive toxicant in vivo. Increases in biliary inorganic phosphate (P(i)) and glucose occur prior to biliary epithelial cell (BEC) injury, which could be due to increased paracellular permeability and/or impairment of P(i) and glucose uptake by BEC. To evaluate these possibilities, we induced mild injury [loss of BEC from major bile ducts (6 h), ultrastructural alterations in BEC mitochondria and Golgi cisternae (3 h), and striking increases in biliary P(i) and glucose (3-6 h)] with 25 mg DAPM/kg and then assessed temporal alterations in tight junction (TJ) permeability by measuring bile to plasma (B:P) ratios of [(3)H]-inulin. Parameters maintained by hepatocytes in bile were unchanged (bile flow, bile salts, bilirubin) or only transiently perturbed (protein, glutathione). Minimal elevations in B:P ratios of inulin occurred temporally later (4 h) in DAPM-treated rats than increases in biliary P(i) and glucose. To confirm a direct effect of DAPM on BEC TJs, we measured transepithelial resistance (TER) and bi-ionic potentials of BEC monolayers prior to and after exposure to pooled (4-6) bile samples collected from untreated rats (Basal Bile) or rats treated with 50 mg DAPM/kg (DAPM-Bile). BEC TJs were found to be cation selective. Exposure to DAPM-Bile for 1 h decreased TERs by approximately 35% and decreased charge selectivity of BEC TJs while exposure to Basal Bile had no effects. These observations indicate that DAPM-Bile impairs paracellular permeability of BEC in vitro. Further, our in vivo model suggests that increases in paracellular permeability induced by DAPM are localized to BEC because bile flow and constituents excreted by hepatocytes were unchanged, BEC damage was temporally correlated with increases in biliary P(i) and glucose, and elevations in B:P ratios of inulin were delayed and minimal.

Aniline Compounds↗

PubMed1996

Agents for the treatment of overactive detrusor. IX. Synthesis and pharmacological properties of metabolites of N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine (FK584) in human urine.

We synthesized the racemates of the five presumed metabolites (1b-f) of (S)-(--)-N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (FK584, S(--)-1a), a novel agent for the treatment of overactive detrusor syndrome, in order to confirm the structures of the metabolites and also to evaluate their inhibitory activity against detrusor contraction. (+/-)-N-tert-Butyl-4-(4-hydroxyphenyl)- and 4-(4-hydroxyphenyl)- and 4-phenyl-2-cyclopentenylamines (1b--e) were synthesized via 5-(4-methoxyphenyl)- and 5-(4-benzyloxy-3-methoxyphenyl)-5-phenyl-2-cyclopenten-1-one (9g, h), respectively. Compounds 1b-f prepared in this study were identical with the metabolites in human urine in gas chromatography-mass spectrometry and analytical HPLC. The inhibitory activity of compounds 1b-f against detrusor contraction in vitro induced by electrical field stimulation in guinea-pigs was less potent than that of FK584.

Amines↗