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PubMed1977

Epidermal hyperplasia after topical application of benzo (a) pyrene, benzo (a) pyrene diol epoxides, and other metabolites.

The effects of benzo(a)pyrene (BP) and 22 derivatives upon the number of nuclei per unit length of epidermis, the number of cell layers of epidermis, and the thickness of the epidermal layer were studied. Several derivatives of BP induced changes in epidermal morphology that are typical of those produced by various agents that promote skin tumorigenesis after application of an initiator. The most potent compounds tested were the BP diol epoxides, (+/-)-7beta,8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo-(a)pyrene (diol epoxide 1) and (+/-)-7beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol epoxide 2). These derivatives were followed in activity by 9-hydroxybenzo(a)pyrene, 2-hydroxybenzo(a)pyrene, and by 9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. The possible implications of these results with regard to the carcinogenicity of BP on mouse skin are discussed.

Administration, Topical↗
PubMed2004

Electron ionization mass spectral fragmentation of derivatized 4,5- and 5,6-epoxysterols.

The electron ionization (EI) mass spectral fragmentation of derivatized 4,5- and 5,6-epoxysterols was investigated. Interesting fragmentation processes involving a transannular cleavage of the epoxide ring after transfer of the trimethylsilyl group are significant in the case of 4,5-epoxysterol trimethylsilyl ethers (affording abundant fragment ions at m/z 403 and 404). Different pathways, which have been substantiated by deuterium labelling, are proposed in order to explain the formation of these ions. In contrast, this transfer is not significant in the case of 5,6-epoxysterol trimethylsilyl ethers. The EI mass spectra of these latter compounds appear to be very complex and to differ slightly according to the stereochemistry of the epoxy group. Acetate and trifluoroacetate derivatives of 4,5-epoxysterols display interesting EI mass spectra dominated by a fragment ion at m/z 332 resulting from cleavage of the steroid ring A.

Cholestanol↗
PubMed1984

The mutagenicity of mono- and di-functional aromatic glycidyl compounds.

Although epoxides are very important compounds in today's technology, they are not as well investigated for their carcinogenic and mutagenic properties as their economical importance would suggest. The present study tried, on one hand, to bridge the gap between microbial testing of such compounds and the in vivo mammalian test system. On the other hand, the comparative testing of structurally related substances was expected to yield some clues as to the structural determinants of possible in vivo mutagenic activity. Our investigations with 4 compounds of similar structure, namely glycidylmethylaniline (GMA), diglycidylaniline (DGA), phenylglycidylether (PGE), and resorcinol diglycidyl ether (RDGE), first demonstrated that, in bacterial assays, all 4 epoxides acted as potent mutagens. Only the 2 difunctional epoxides, however, were active in an in vitro chromosomal aberration assay with CHO cells. That such in vitro results cannot be supposed to represent the in vivo situation is again demonstrated by discovery that only one of the two in vitro active substances (and in fact it is the less active one) also has a damaging effect in vivo. It, therefore, seems quite justifiable to conclude that two structural features must be combined in an aromatic glycidyl compound if it is to exert chromosome damaging activity in vivo: The substance must possess 2 epoxy functions, and they must be bound to the aromatic nucleus by an aminic nitrogen. The industrial use of aromatic glycidyl ethers might, therefore, be considered not to pose a great systemic risk for mutagenicity or carcinogenicity, without completely excluding the possibility of local effects.

Animals↗
PubMed2005

Stability of silorane dental monomers in aqueous systems.

UNLABELLED: Siloranes (silicon-based monomers with oxirane functionality) are investigated as matrix resins for new low shrinkage/stress dental composites. Compounds containing oxirane groups are known to be reactive with water, which could impart instability to the composite. OBJECTIVE: To test the stability of siloranes by measuring changes in the chemical structure of the oxirane group in aqueous environments. METHODS: Two siloranes (PH-SIL and TET-SIL) and their 1:1 mixture (SIL-MIX) were evaluated (n=2-3). Siloranes were mixed in aqueous solutions with and without 1% tetrahydrofuran (THF) containing either liver esterase or epoxide hydrolase at pH 7.4, or dilute HCl at pH 1.4. The stability of conventional dioxiranes 3,4-epoxycyclohexyl-methyl-3,4-epoxycyclohexane carboxylate (ECHM-ECHC), and bisphenol A diglycidyl ether (BADGE) were also monitored under similar conditions. NMR was used to estimate the extent of reaction and give structural information about reaction products. RESULTS: Siloranes were found to be stable for 24h in all aqueous environments tested. In contrast, ECHM-ECHC reacted at pH 1.4 to form species containing oxirane, ester, hydroxyl and carboxylic acid groups. Water hydrolyzed the ester group of ECHM-ECHC in the presence of liver esterase. In the presence of epoxide hydrolase, BADGE oxirane groups were hydrolyzed to diols, hydrolysis ranged from 0 to 34% depending on the aqueous environment. CONCLUSION: The stability and insolubility of siloranes in biological fluid simulants suggests that these may be more suitable for use in the oral environment than conventional oxirane-functional monomers.

Benzhydryl Compounds↗
PubMed2005

Carboxylate-stabilised sulfur ylides (thetin salts) in asymmetric epoxidation for the synthesis of glycidic acids. Mechanism and implications.

The reaction of carboxylate-stabilised sulfur ylides (thetin salts) with aldehydes and ketones has been investigated. Using both achiral and chiral sulfur ylides, good yields were obtained with dimsylsodium or LHMDS as bases in DMSO or THF-DMSO mixtures. However, the enantioselectivities observed with a camphor-based sulfide were only moderate (up to 67%). The reaction was studied mechanistically by independent generation of the betaine (via the hydroxyl sulfonium salt) in the presence of a more reactive aldehyde, which resulted in incorporation of the more reactive aldehyde and showed that betaine formation was reversible. Thus, the moderate enantiomeric excess observed is a consequence of the enantiodifferentiating step being the ring closure step rather than the betaine forming step. We had expected betaine formation might be non-reversible because a carboxylate-stabilised ylide has only slightly higher stability than a phenyl-stabilised ylide, which does largely react non-reversibly with aldehydes. Evidently, a carboxylate-stabilised ylide is significantly more stable than a phenyl-stabilised ylide and as such reacts reversibly with aldehydes.

Amides↗
PubMed2002

Bisphenol A diglycidyl ether induces apoptosis in tumour cells independently of peroxisome proliferator-activated receptor-gamma, in caspase-dependent and -independent manners.

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors which are involved in many biological processes, such as regulation of cell differentiation, lipid metabolism, inflammation and cell death. PPARs consist of three families, PPAR-alpha, PPAR-delta and PPAR-gamma. Bisphenol A diglycidyl ether (BADGE) has been described as a pure antagonist of PPAR-gamma. However, recent data also revealed PPAR-gamma-agonistic activities of BADGE. Here we show that BADGE kills transformed cells by apoptosis and promotes the cytotoxic effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and indomethacin. The cytotoxic effect of BADGE does not require PPAR-gamma expression and is mediated in caspase-dependent and caspase-independent manners.

Apoptosis↗
PubMed2000

Dermal penetration and metabolism of five glycidyl ethers in human, rat and mouse skin.

1. Glycidyl ethers (GE), an important class of industrial chemicals, are considered to be potentially mutagenic in vivo because some GE have been shown to be direct mutagens in short-term in vitro tests. 2. The percutaneous penetration and metabolism of representatives of different classes of GE was studied in the fresh, full-thickness C3H mouse, and dermatomed human and Fisher 344 rat skin to determine the apparent permeability constants, lag times and metabolic profiles. 3. Five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), were synthesized by reaction of their alcohols with epichlorohydrin. Their radiolabelled analogues were synthesized with a 14C-label using [U-14C]-epichlorohydrin. 4. There was a large variation (four orders of magnitude) in percutaneous penetration between the five GE. In general, penetration through full-thickness mouse skin was higher than through dermatomed rat skin, whereas dermatomed human skin was the least permeable. The permeability increased in the order YX4000 < BADGE < C12GE < o-CGE < HDDGE. 5. The relative skin permeability of the five GE could be explained for a significant part by the lipophilicity, expressed as log P(o/w), in combination with the molecular weight of the compounds. 6. During skin penetration, all GE were extensively metabolized to their corresponding (bis-)diols. Virtually no YX4000, and only very small amounts of C12GE and BADGE, penetrated the skin unchanged, but significant amounts of HDDGE and o-CGE penetrated the skin unchanged. For o-CGE, but none of the other GE, the percentage of the applied dose that penetrated the skin unchanged increased over time. 7. The large variation in response observed with the five selected GE indicates that GE should not be considered as a single class of compounds but rather on the basis of their individual properties.

Animals↗
PubMed2001

Chlorohydrins of bisphenol A diglycidyl ether (BADGE) and of bisphenol F diglycidyl ether (BFDGE) in canned foods and ready-to-drink coffees from the Japanese market.

BADGE.2HCl and BFDGE.2HCl were determined in 28 samples of ready-to-drink canned coffee and 18 samples of canned vegetables (10 corn, 5 tomatoes and 3 others), all from the Japanese market. HPLC was used as the principal analytical method and GC-MS for confirmation of relevant LC fractions. BADGE.2HCl was found to be present in one canned coffee and five samples of corn, BFDGE.2HCl in four samples of canned tomatoes and in one canned corn. No sample was found which exceeded the 1 mg/kg limit of the EU for the BADGE chlorohydrins. However the highest concentration was found for the sum of BFDGE.2HCl anti BFDGE.HCl.H2O at a level of 1.5 mg/kg. A Beilstein test confirmed that all cans containing foods contaminated with BADGE.2HCl or BFDGE.2HCl had at lest one part coated with a PVC organosol.

Benzhydryl Compounds↗
PubMed2005

Dietary exposure to chemical migrants from food contact materials: a probabilistic approach.

A two-dimensional probabilistic model has been developed to estimate the short-term dietary exposure of UK consumers to migrants from food packaging materials. The current EU approach uses a default scenario of assuming that all individuals are 60 kg weight and consume 1 kg of food packaged in the material of interest per day. Using four UK National Dietary and Nutrition Surveys comprising 4-7 day dietary records for different age groups and survey years, a sample representative of the UK population has been obtained consuming around 4200 different food items. Each survey provides records for around 2000 individuals and supplies detailed information on the consumption of food and data on sex, height and socio-economic status which may be used to analyse the exposure of selected groups within the community. As a result we are able to address the variation in consumption of food amongst individuals, and account for actual body weights providing a more accurate representation of the 'true' exposure. The migrants bisphenol A diglycidyl ether (BADGE), di-2-ethylhexyl adipate (DEHA) and styrene were considered as specimen compounds although the methodology employed has the flexibility to adapt to other migrants and packaging types and indeed other food contaminants. Exposure for each individual is estimated by calculating and summing the individual exposure from each item in their diet, and is repeated for all individuals in each survey to produce a distribution of exposures for the population. The packaging type of each food item is assigned by utilizing known packaging types from the database or, by sampling from a distribution based upon market share information. The parameters contributing towards the exposure from a packaged dietary item are migrant concentration and item weight. Distributions are used to represent the inherent variation and uncertainty affecting these parameters. Where data on concentrations for a particular type of food are lacking, expert judgement is used to extrapolate from available data for other food types. The model can also be run using only migration data for food simulants. In this case, concentrations expected for each of the food items are assigned based on the data for the relevant food simulant. The primary outputs of the model are distributions of estimated daily intakes for the selected population. Each distribution gives the variation across the population subject to the uncertain parameters sampled in that iteration of the model. Analysing the ensemble of distributions allows us to obtain the confidence limits around estimates for percentiles due to the uncertainties. The probabilistic approach allows sensitivity analysis to evaluate the relative importance of the input parameters and places confidence bounds on the outputs to show the effect of the uncertainties and the contribution of each food type toward the overall exposure.

Adipates↗
PubMed2000

Epoxide formation from diallyl sulfone is associated with CYP2E1 inactivation in murine and human lungs.

We tested the hypothesis that an epoxide formed from diallyl sulfone (DASO(2)) is responsible for inactivation of CYP2E1 in murine and human lungs. An epoxide (1,2-epoxypropyl-3,3'-sulfonyl-1'-propene [DASO(3)]) was synthesized from DASO(2) and conjugated with glutathione (GSH) to produce the conjugates S-(1R, S-[[1-hydroxymethyl-2,3' -sulfonyl]-1' -propenyl]ethyl)glutathione (diastereomers) and S-(1-[[2R,S-hydroxypropyl]-3, 3'-sulfonyl]-1'-propenyl)glutathione (diastereomers). Analysis of these conjugates by high performance liquid chromatography revealed a major peak eluting at 20.5 min. This peak was detected in incubations of murine and human lung microsomes containing DASO(2) and nicotinamide adenine dinucleotide phosphate (NADPH), and was not detected in incubations performed in the absence of DASO(2) or NADPH. The amounts of epoxide-derived GSH conjugates formed in the incubations were concentration-dependent and achieved saturation at 0.75 mM DASO(2). Formation of the conjugates was also time-dependent and peaked at 2.0 h after DASO(2). The peak containing the GSH conjugates was also detected in incubations of CYP2E1-expressed lymphoblastoid microsomes, NADPH, and DASO(2). Maximal amounts of DASO(3), as estimated by formation of a 4-(p-nitrobenzyl)pyridine derivatized product, were detected in murine lung microsomes incubated for 35 min with 1 mM DASO(2). The derivatized DASO(3) was not detectable in incubations of human lung microsomes. p-Nitrophenol hydroxylation, a catalytic activity associated with CYP2E1, was reduced in murine and human lung microsomes incubated with DASO(2), with decreases that were concentration-dependent. Dose-dependent decreases in hydroxylase activity were also found in microsomes from mice treated in vivo with DASO(2) (25 to 200 mg/kg). These results supported the premise that an epoxide formed from DASO(2) mediates inactivation of lung CYP2E1. Furthermore, the findings suggested that the mouse model is relevant for studies of DASO(2) in human lung.

Allyl Compounds↗
PubMed1988

Depletion of hepatic non-protein sulfhydryl content during exposure of rats and mice to butadiene.

B6C3F1 mice, Sprague-Dawley and Wistar rats were exposed to 1,3-butadiene in a closed exposure system. Exposure concentrations were kept above 2000 ppm to ensure saturation of butadiene metabolism in both species (Vmax conditions). Hepatic non-protein sulfhydryl (NPSH) content was determined in butadiene-exposed animals (and air-exposed controls) after exposures for 0, 7 and 15 h. Depletion of hepatic NPSH content was different for the species and strains investigated. In mice, hepatic NPSH content declined to about 20% after 7 h and was further depleted to about 4% at 15 h when signs of acute toxicity were observed. After a 7 h exposure of rats to butadiene, hepatic NPSH content was depleted to about 65% (Wistar) or 80% (Sprague-Dawley) of the corresponding controls but remained practically stable after a 15 h exposure to butadiene. The time-courses of depletion by butadiene of hepatic NPSH support previous findings on differences in butadiene metabolism between rats and mice and offer an additional explanation for the considerable species differences observed in the toxicity and carcinogenicity of this compound.

Animals↗
PubMed1965

AN ENZYME CATALYSING THE CONJUGATION OF EPOXIDES WITH GLUTATHIONE.

1. Liver supernatant preparations from rats and ferrets catalyse the conjugation of some epoxides with glutathione. The enzyme involved might be called ;glutathione S-epoxidetransferase', as it is different from glutathione S-aryltransferase, the enzyme catalysing the conjugation of 1,2-dichloro-4-nitrobenzene, 4-nitro-pyridine N-oxide and other cyclic compounds with glutathione and from the enzyme catalysing the conjugation of iodomethane and glutathione. 2. The enzyme does not catalyse the reaction with cysteine. It is not inactivated by dialysis but is unstable at pH 5.0. 3. The role of the enzyme in metabolism of foreign compounds is discussed.

Carnivora↗
PubMed1965

METABOLISM OF POLYCYCLIC COMPOUNDS. THE METABOLISM OF 9,10-EPOXY-9,10-DIHYDROPHENANTHRENE IN RATS.

1. 9,10-Epoxy-9,10-dihydrophenanthrene is converted by rats into trans-9,10-dihydro-9,10-dihydroxyphenanthrene and its conjugates and into N-acetyl-S-(9,10-dihydro-9-hydroxy-10-phenanthryl)-l- cysteine. Small amounts of 9-phenanthryl sulphate and glucosiduronate are also formed, together with 9-hydroxy-10-phenanthryl sulphate. 2. The epoxide readily rearranges to 9-hydroxyphenanthrene and reacts with water to give the dihydrodihydroxy compound and with N-acetylcysteine to give the mercapturic acid. One of the diastereoisomeric forms of the methyl ester of the mercapturic acid is identical with the ester of the mercapturic acid excreted by rats dosed with the epoxide or by rats and rabbits dosed with phenanthrene. 3. A rat-liver homogenate converts the epoxide into trans-9,10-dihydrodihydroxyphenanthrene and S-(9,10-dihydro-9-hydroxy-10-phenanthryl)glutathione. The latter compound was not formed when boiled rat-liver homogenate was used, but was formed chemically from the epoxide and glutathione under more vigorous conditions. 4. The results provide further indications that the metabolism of aromatic hydrocarbons involves the intermediary formation of epoxides.

Acetylcysteine↗
PubMed2001

Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins.

Epidemiological data suggest that dietary antioxidants play a protective role against cancer. This has led to the proposal that dietary supplementation with antioxidants such as vitamin C (vit C) may be useful in disease prevention. However, vit C has proved to be ineffective in cancer chemoprevention studies. In addition, concerns have been raised over potentially deleterious transition metal ion-mediated pro-oxidant effects. We have now determined that vit C induces lipid hydroperoxide decomposition to the DNA-reactive bifunctional electrophiles 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal. The compound 4,5-Epoxy-2(E)-decenal is a precursor of etheno-2'-deoxyadenosine, a highly mutagenic lesion found in human DNA. Vitamin C-mediated formation of genotoxins from lipid hydroperoxides in the absence of transition metal ions could help explain its lack of efficacy as a cancer chemoprevention agent.

Aldehydes↗
PubMed2005

Azinomycin inspired bisepoxides: influence of linker structure on in vitro cytotoxicity and DNA interstrand cross-linking.

A series of bisepoxides based on the epoxide domain of the naturally occurring azinomycins have been synthesised. The incorporation of an aminomethyl group into the linker between the two alkylating epoxide units is shown to significantly enhance in vitro cytotoxicity against human tumour cell lines and DNA interstand cross-linking efficiency.

Anti-Bacterial Agents↗