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PubMed1990

A fluorescence study of the binding of Hoechst 33258 and DAPI to halogenated DNAs.

We have studied the time-resolved and the steady-state fluorescence of the DNA groove binders 4',6-diamidino-2-phenylindole (DAPI) and Hoechst 33258 with the double stranded DNAs poly(dA-dU) and poly(dI-dC) and their halogenated analogs, poly(dA-I5dU) and poly(dI-Br5dC). These studies were prompted by earlier observations that steady-state fluorescence of Hoechst 33258 is quenched on binding to halogenated DNAs (presumably due to an intermolecular heavy atom effect involving the halogen atom in the major groove), and recent studies which clearly point to a binding-site in the minor groove of DNA. Measurements of the time resolved fluorescence decay demonstrate that the fluorescence of Hoechst 33258 is quenched on binding to the halogenated DNAs, in agreement with previous observations. However, quenching studies carried out using the free halogenated bases IdUrd and BrdCyd in solution yielded bimolecular rate constants more than one order of magnitude larger than those expected for an intermolecular heavy atom effect. Moreover, the quenching of the Hoechst 33258 fluorescence was accompanied by an accelerated photochemical destruction of Hoechst 33258. We therefore conclude that the fluorescence quenching observed with halogenated DNAs is probably due to a photochemical reaction involving Hoechst 33258, rather than direct contact of Hoechst 33258 with the halogen substituents in the major groove of the DNA. The fluorescence decay measurements however, do provide clear evidence for at least two different modes of binding. Taking into account the alternating sequences used in this study and the possibility of two different conformations for bound dye, at least four different modes of binding are plausible. Our present data do not allow us to distinguish between these alternatives. The time-resolved fluorescence decays and fluorescence quantum yields of DAPI are not affected by the presence of the heavy atom substituents in the DNA major groove. Based on this observation and earlier reports that DAPI binds in one of the DNA grooves, we conclude that the high affinity sites for DAPI on DNA are located in the minor groove.

Benzimidazoles↗

PubMed2003

Unexpected differences in the alpha-halogenation and related reactivity of sulfones with perhaloalkanes in KOH-t-BuOH.

Most alkyl phenyl sulfones are readily alpha-chlorinated with CCl(4) and alpha-brominated with CBrCl3 in KOH-t-BuOH via radical-anion radical pair (RARP) reactions. While isopropyl mesityl sulfone (4) is easily alpha-chlorinated with CCl(4), it was completely recovered when treated with the more reactive CBrCl3. Subsequent investigations showed the latter result to be due to the poor acidity of 4 together with the rapid depletion of CBrCl3 and KOH by their reaction with each other, and led to a variety of other important results. 4-Hydroxyphenyl isopropyl sulfone (6) is unreactive with either CCl4 or CBrCl3 in KOH-t-BuOH, its phenoxide anion strongly reducing the electronegativity of the sulfonyl group, thereby inhibiting alpha-anion formation. This effect is reversed by the electron-withdrawing influence of two alpha-phenyls, so that benzhydryl 4-hydroxyphenyl sulfone (8) is readily alpha-halogenated in KOH-t-BuOH with CCl4 or CBrCl3. On further contact with KOH-t-BuOH the alpha-halogenated sulfones from 8 are decomposed into benzophenone and phenol. While the alpha-halogenated derivatives of 4-methoxyphenyl benzhydryl sulfone (9) are stable to base, they are decomposed even under mildly acidic conditions into 4-methoxyphenyl 4-methoxybenzenethiolsulfonate (9c), phenol, and benzophenone. Mono-alpha-halogenation of benzyl phenyl sulfone (10) enhances the rate of the subsequent halogenation, so that alpha,alpha-dihalogenation is attained while much substrate is still present and the mono-alpha-halogenated product is not detected. The ease of reductive debromination of alpha-bromo sulfones with Cl3C- was correlated with the stability of the formed alpha-anions, explaining the success with alpha-bromobenzylic sulfones but failure with alpha-bromoalkyl sulfones. In the presence of air and the absence of competing halogenation, formation of the alpha-anions of alkyl aryl sulfones is quickly accompanied by oxidative cleavage by atmospheric O2, leading to the formation of arenesulfonyl alcohols, arenesulfonyl halides, and haloarenes.

Journal Article↗

PubMed1981

Halogenation and topical corticosteroids: a comparison between the 17-butyrate esters of hydrocortisone and clobetasone in ointment bases.

Clobetasone butyrate 0.05% (Eumovate), a halogenated topical steroid, was compared with hydrocortison butyrate 0.1% (Locoid) which does not contain any halogen atoms. In the treatment of eczema there was not difference between the preparations, but in that of psoriasis the halogen-containing steriod was significantly more effective. Under normal circumstances neither preparation had any detectable effect on adrenal function, but with large doses under total-body polythene occlusion, circulating cortisol levels were reduced less by the halogenated than by the non-halogenated preparation. Corticosteroids which contain a halogen atom are often considered to cause more adverse effects than the non-halogenated preparations with similar clinical efficacy. This study shows that this cannot be assumed for their ability to suppress cortisol levels.

Administration, Topical↗

PubMedDate not supplied

Supercritical fluid extraction of halogenated monoterpenes from the red alga Plocamium cartilagineum.

Supercritical fluid extraction (SFE) of the marine red alga Plocamium cartilagineum, which is known to contain complex mixtures of halogenated monoterpenes, was investigated. P. cartilagineum samples were extracted by SFE with carbon dioxide and modified carbon dioxide containing up to 10% methanol at different pressure and temperature conditions to establish the optimum conditions for extraction. These conditions were then used in the extraction of halogenated monoterpenes from 2 different samples of P. cartilagineum: one from Davenport, CA, and the other from Casa Beach (San Diego, CA). Several halogenated monoterpenes isolated by conventional solvent extraction with methanol and purified by column chromatography were used as the reference compounds for the determination of the extraction efficiency in the SFE experients. Plocamium cartilagineum belongs to the red alga family--Plocamiaceae, and has been found to contain a large number of halogenated monoterpenes, whose structures typically contain 1-6 bromine and/or chlorine atoms. P. cartilagineum grows along the Pacific coast from Washington to Chile, the British Isles, Australia, and Spain. Interestingly, P. cartilagineum collected from different geographical areas in the world are all reported to produce halogenated monoterpenes, but of different structural types and halogen substitution patterns. Most of these halogenated monoterpenes have been found to exhibit varied biological activities, including antifungal, antimicrobial, and molluscicidal activity.

Carbon Dioxide↗

PubMed2006

An overview of halogen bonding.

Halogen bonding (XB) is a type of noncovalent interaction between a halogen atom X in one molecule and a negative site in another. X can be chlorine, bromine or iodine. The strength of the interaction increases in the order Cl<Br<I. After a brief review of experimental evidence relating to halogen bonding, we present an explanation for its occurrence in terms of a region of positive electrostatic potential that is present on the outermost portions of some covalently-bonded halogen atoms. The existence and magnitude of this positive region, which we call the sigma-hole, depends upon the relative electron-attracting powers of X and the remainder of its molecule, as well as the degree of sp hybridization of the s unshared electrons of X. The high electronegativity of fluorine and its tendency to undergo significant sp hybridization account for its failure to halogen bond. Some computed XB interaction energies are presented and discussed. Mention is also made of the importance of halogen bonding in biological systems and processes, and in crystal engineering.

Halogens↗

PubMed2006

Comparison of bond strength between orthodontic brackets bonded with halogen and plasma arc curing lights: an in-vitro and in-vivo study.

INTRODUCTION: This study assessed in-vitro shear bond strength and in-vivo survival rate of orthodontic brackets bonded with either a halogen or a plasma arc light. METHODS: Ninety extracted premolars were divided into 6 groups of 15. Stainless steel brackets were bonded to the teeth by using either a halogen light with a 20-second curing time or a plasma arc light with a 2-, 6-, or 10-second curing time. Brackets were debonded either within 30 minutes of bonding or after thermocycling for 24 hours. Bond strengths were tested on a testing machine at a crosshead speed of 1 mm/minute. The bracket failure interface was measured with a modified adhesive remnant index score. Data were analyzed by using ANOVA and Tukey-Kramer multiple comparison tests. For the in-vivo study, a split-arch design was used to determine the bracket-failure rate and distribution in 25 patients. The patients were followed for a mean period of 1.1 years (386 days). Survival analysis was carried out to compare the failure rates of the 2 techniques. RESULTS: No significant differences in bond strengths were found 30 minutes after bonding between the halogen light (13.6 +/- 3.8 MPa) and the plasma arc light with 2-, 6-, or 10-second curing times (9.6 +/- 2.9, 14.2 +/- 4.6, 16.0 +/- 3.0 MPa, respectively). Similar bond strengths were also found between the halogen light with a 20-second (16.1 +/- 3.6 MPa) curing time and plasma arc light with 6 seconds (18.2 +/- 4.6 MPa) of curing time after 24 hours of thermocycling. For the in-vivo study, no significant difference was found in bracket failure rates between the 2 light sources (4.9% in both groups). No significant differences were found between ARI scores for the halogen light and the plasma arc light at either 30 minutes or 24 hours after debonding. CONCLUSIONS: These results indicate that the plasma arc light with a 6-second curing time can produce similar bond strength and bracket-failure rates as the halogen light that requires a longer curing time.

Adhesives↗

PubMed2005

Light-curing time reduction with a new high-power halogen lamp.

INTRODUCTION: Orthodontic brackets are routinely bonded with light-cured adhesives. Conventional halogen lights used in bonding have the disadvantage of a long curing time, and the available alternatives (laser and plasma lights) are expensive. Our aim was to investigate the minimum time necessary to bond brackets with a new, relatively low-priced, high-power halogen light. METHODS: Five groups of 15 deciduous bovine incisors were bonded with stainless steel brackets (Mini Diamond Twin, Ormco, Orange, Calif) by using different lamps and curing times. Three of the groups were bonded by using a high-power halogen light (Swiss Master Light, Electro Medical Systems, Nyon, Switzerland) for 2, 3, and 6 seconds, respectively. The fourth group, bonded with a fast halogen light (Optilux 501, Sybron Dental Specialties, Danbury, Conn) for 40 seconds, served as the positive control group. The fifth group, the comparison group, was bonded with a plasma light (Remecure, Remedent, Deurle, Belgium) for 4 seconds. After storage for 24 hours in the dark at 37 degrees C in water, shear bond strength was measured with a universal testing machine. RESULTS: A curing time of 2 seconds with the high-power halogen light negatively affected the bond strength and the probability of bond survival. The adhesive remnant index scores were not significantly different among the groups. Most failures (> 60%) occurred at the bracket base/adhesive interface. CONCLUSIONS: The high-power halogen light seems to be a cost-effective solution to reducing curing time. The recommended curing times to bond stainless steel brackets are 6 seconds and, with caution, even 3 seconds.

Analysis of Variance↗

PubMed2005

Screening of organic halogens and identification of chlorinated benzoic acids in carbonaceous meteorites.

The occurrence of halogenated organic compounds measured as a sum parameter and the evidence of chlorinated benzoic acids in four carbonaceous meteorites (Cold Bokkeveld, Murray, Murchison and Orgueil) from four independent fall events is reported. After AOX (Adsorbable organic halogen) and EOX (Extractable organic halogen) screening to quantify organically bound halogens, chlorinated organic compounds were analyzed by gas chromatography. AOX concentrations varying from 124 to 209 microg Cl/g d.w. were observed in carbonaceous meteorites. Ion chromatographic analysis of the distribution of organically bound halogens performed on the Cold Bokkeveld meteorite revealed that chlorinated and brominated organic compounds were extractable, up to 70%, whereas only trace amounts of organofluorines could be extracted. Chlorinated benzoic acids have been identified in carbonaceous meteorite extracts. Their presence and concentrations raise the question concerning the origin of halogenated, especially chlorinated, organic compounds in primitive planetary matter.

Carbon↗

PubMed2004

An investigation of halogens in Izmit hazardous and clinical waste incinerator.

In the combustion facilities, halogens (Cl, F, Br, I) should be considered with regard to the control of the compounds such as polychlorinated dibenzodioxins (PCDD), polychlorinated dibenzofurans (PCDF), halogenated polyaromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and volatile heavy metals formed as a result of incomplete combustion and caused adverse environmental effects. In this study halogens were observed in Izmit Hazardous and Clinical Waste Incinerator (IZAYDAS). Halogen contents of the combustion menu, flue gas, fly ash, bottom ash and filter cake were measured and their distributions in these exit streams were determined. Results showed that the major part of the halogens was partitioned to solid residues, i.e., bottom ash and filter cake which represents the removal by wet scrubbers. Fly ash and flue gas fractions of halogens were much lower due to the reduced formation of volatile compounds.

Air Pollutants↗

PubMed2003

Identification and quantification of mutagenic halogenated cytosines by gas chromatography, fast atom bombardment, and electrospray ionization tandem mass spectrometry.

Oxidative modification of nucleic acids has been implicated in carcinogenesis. One potential mechanism involves halogenation by the myeloperoxidase and eosinophil peroxidase systems of phagocytes. In the current studies, three mass spectrometric methods for the in vitro and in vivo analysis of halogenated cytosines and deoxycytidines were compared: gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) with a quadrupole instrument, fast atom bombardment or electrospray ionization (ESI) tandem MS with a four-sector magnetic instrument, and liquid chromatography ESI tandem MS (HPLC-ESI-MS/MS) with an ion-trap instrument. GC-EI-MS with selected ion monitoring of dimethyl-tert-butylsilyl derivatives of nucleobases was the most sensitive method. High-energy collisionally induced dissociation MS/MS analysis with a four-sector magnetic instrument yielded detailed structural information about halogenated nucleoside adducts but required relatively large amounts of material. The most sensitive analysis of intact halogenated deoxycytidine was achieved with extracted ion chromatograms using HPLC-ESI-MS/MS with an ion-trap instrument. Our results indicate that GC-EI-MS is the methodology of choice for ultrasensitive analysis of halogenated cytosines. HPLC-ESI-MS/MS provides greater structural detail for these compounds and may rival GC-EI-MS in sensitivity with more advanced liquid chromatography applications. The mass spectrometric methods we have developed should be useful for evaluating the role of phagocyte-derived oxidants in halogenating nucleobases, nucleosides, and DNA at sites of inflammation.

Bromodeoxycytidine↗

PubMed2003

The role of halogen species in the troposphere.

While the role of reactive halogen species (e.g. Cl, Br) in the destruction of the stratospheric ozone layer is well known, their role in the troposphere was investigated only since their destructive effect on boundary layer ozone after polar sunrise became obvious. During these 'Polar Tropospheric Ozone Hole' events O(3) is completely destroyed in the lowest approximately 1000 m of the atmosphere on areas of several million square kilometres. Up to now it was assumed that these events were confined to the polar regions during springtime. However, during the last few years significant amounts of BrO and Cl-atoms were also found outside the Arctic and Antarctic boundary layer. Recently even higher BrO mixing ratios (up to 176 ppt) were detected by optical absorption spectroscopy (DOAS) in the Dead Sea basin during summer. In addition, evidence is accumulating that BrO (at levels around 1-2 ppt) is also occurring in the free troposphere at all latitudes. In contrast to the stratosphere, where halogens are released from species, which are very long lived in the troposphere, likely sources of boundary layer Br and Cl are autocatalytic oxidation of sea salt halides (the 'Bromine Explosion'), while precursors of free tropospheric BrO and coastal IO probably are short-lived organo-halogen species. At the levels suggested by the available measurements reactive halogen species have a profound effect on tropospheric chemistry: In the polar boundary layer during 'halogen events' ozone is usually completely lost within hours or days. In the free troposphere the effective O(3)-losses due to halogens could be comparable to the known photochemical O(3) destruction. Further interesting consequences include the increase of OH levels and (at low NO(X)) the decrease of the HO(2)/OH ratio in the free troposphere.

Atmosphere↗

PubMed2004

The influence of storage and indenter load on the Knoop hardness of dental composites polymerized with LED and halogen technologies.

OBJECTIVES: The mechanical properties of light cured dental composites are greatly influenced by the light curing unit (LCU) used for the polymerization. Previous studies have shown that for some composites lower mechanical properties were obtained if light emitting diode (LED) LCUs were used for the polymerization instead of halogen LCUs. Previous studies have also shown that light cured composites improve their mechanical properties through a post-curing process after the initial illumination with the LCUs. Therefore, this study investigated the post-curing process, to ascertain if it can compensate for the lower mechanical properties of composites polymerized with LED LCUs. METHODS: The Knoop hardness was measured for four dental composites (Z100, Spectrum, Definite, Solitaire2) polymerized with an LED LCU (LED63 prototype) or a halogen LCU (Trilight), directly after the curing process and after 5 days of storage. In addition, the load on the indenter was varied from 200 to 400 gf to investigate the influence of the load on the measured hardness on the top and bottom of the 2 mm thick samples. RESULTS: In general the Knoop hardness at the bottom of the stored samples, cured with the LED LCU, was the same or statistically significantly greater than for the samples cured with the halogen LCU. A statistically significantly lower (p<0.0001) Knoop hardness was obtained on the top of the samples if the composite Definite was polymerized with the LED LCU instead of the halogen LCU. The load of 200 or 400 gf on the indenter had a statistically significant influence (p<0.0001) on the measured Knoop hardness for the composite Z100. The Knoop hardness measured with an indenter load of 400 gf increased statistically significantly (p<0.0001) for all composites after the 5 days' storage, whether cured with the LED LCU or halogen LCU. SIGNIFICANCE: The post-curing effect cannot compensate for the lower hardness of composites containing co-initiators if polymerized with an LED LCU instead of a halogen LCU. The indenter load had a statistically significant influence on the measured Knoop hardness of composites and has the potential to falsify results if not selected carefully.

Air↗

PubMed2003

The influence of plasma arc vs. halogen standard or soft-start irradiation on polymerization shrinkage kinetics of polymer matrix composites.

OBJECTIVES: To determine polymerization shrinkage kinetics and hardness of photo-activated polymer matrix composites (PMC) after plasma arc vs. halogen standard or soft-start irradiation. METHODS: Polymerization shrinkage was measured using the 'deflecting disk technique', and Knoop hardness was measured at the bottom of 1.5 mm thick specimens stored for 24 h at 37 degrees C. The materials comprised one micro-filled (Silux Plus) and four fine hybrid PMC (Definite, Herculite XRV, Solitaire 2 and Z250). The irradiation protocols included halogen standard irradiation at three intensities (TriLight, ESPE), ramp curing (dito), step curing (HiLight, ESPE), pulse polymerization (VIP Light, BISCO) and plasma curing (Apollo 95E, DMDS; PAC Light, ADT). RESULTS: Standard halogen irradiation at reduced intensity delayed the start and slowed down the progression of shrinkage strain, but (except for Z250) as well produced lower hardness. Soft-start halogen curing produced similar kinetics but maintained hardness. Plasma arc irradiation resulted in an immediate start and a rapid progression of polymerization contraction, but produced low hardness values in Definite (cured by the ADT unit) and in Solitaire 2 (both units). Z250 featured the highest, Silux Plus the lowest maximum rate of contraction. Despite soft-start irradiation, contraction of Z250 progressed faster than that of Silux Plus with halogen standard irradiation at high intensity. CONCLUSIONS: Soft-start halogen irradiation protocols provide better chances for compensation of shrinkage stress by flow within PMC without compromising hardness and may contribute to a better marginal integrity of the restorations. Irradiation protocols should be individually adjusted to compensate for the different curing characteristics of PMC.

Analysis of Variance↗

PubMed2003

Effects of fast halogen and plasma arc curing lights on the surface hardness of orthodontic adhesives for lingual retainers.

The aims of this study were to (1) identify the optimum cure times of 2 different lingual retainer adhesives with a conventional halogen, a fast halogen, and a plasma arc light by measuring Vickers surface hardness, and (2) determine whether different lights produce similar surface hardness values for the same adhesive resin material. The investigated plasma arc curing unit was the PowerPac (American Dental Technologies, Corpus Christi, Tex), and the fast halogen unit was the Optilux 501 (Kerr, Orange, Calif). A conventional curing unit, the Ortholux XT (3M Dental Products, St. Paul, Minn) was used as the control. Two orthodontic lingual retainer adhesives were used: Transbond Lingual Retainer (3M Unitek, Monrovia, Calif) and Light Cure Retainer (Reliance Orthodontic Products, Itasca, Ill). Concise (3M Dental Products) and diluted Concise were used as controls. Transbond Lingual Retainer was polymerized by the PowerPac light in 6 seconds, by the Optilux in 10 seconds, and by the conventional halogen light in 20 seconds. The minimum curing times for Light Cure Retainer adhesive were 15 seconds for PowerPac, 10 seconds for Optilux, and 40 seconds for conventional halogen. Surface hardness values for each resin did not differ significantly with different curing units. However, different adhesives demonstrated significantly different surface hardness values. Final Vickers surface hardness values (averaged across curing units) of Transbond Lingual Retainer, Concise, diluted Concise, and Light Cure Retainer were 62.8, 52.4, 46.0, and 40.4, respectively. Plasma arc or fast halogen units polymerize resin composite adhesive in much shorter times than do conventional curing units, without a significant loss in surface hardness. Therefore, these units are suggested for clinical use to save chairside time.

Adhesives↗

PubMed1999

Genotoxic effects in bacteria of the light emitted by halogen tungsten lamps having treated quartz bulbs.

Traditional halogen tungsten lamps, which are extensively used worldwide for the illumination of indoor environments, have a quartz bulb which transmits not only visible light but also ultraviolet (UV) light. Due to the output of far-UV wavelengths, halogen lamps were found in previous studies to be potently genotoxic in bacteria, clastogenic in cultured human cells, and carcinogenic in hairless mice. This discovery prompted the launching of new halogen lamps, known as UV-Stop, UV-Block, or similar trade names, which have the quartz glass treated in such a way to reduce its permeability to UV radiation. Surprisingly, these lamps are advertised for attenuating discolouration of UV-sensitive materials, such as fabrics, paintings, works of art and furniture, whereas protection of the human skin from potential carcinogenic risks is overlooked. We tested forty-seven 12 V-powered lamps with treated quartz bulb, which were made available by five producers as blind-coded samples. After exposure to either 1000 lx for 30 min or 2500 lx for 60 min, the 50 W lamps from two producers were borderline mutagenic in strains TA100 and TA104 of S. typhimurium, and induced an evident and dose-related DNA damage in the E. coli strain CM871 (uvrA- recA- lexA-), as compared to its isogenic, DNA repair-proficient counterpart WP2. The 50 W lamps supplied by the other three producers also induced a significant genotoxic damage, but only after exposure for 60 min at illuminance levels of 2500 lx or higher. In calibration experiments, one of these three lamp brands was found to induce in 60 min a genotoxic damage which was equivalent to the one induced in just 55 s by a traditional halogen lamp. Therefore, the new types of lamps with treated quartz bulbs provide an appreciable step forward in the safety of halogen lamps, but some output of genotoxic UV radiations does still occur. Moreover, the lamps manufactured by different producers are not equally effective to this respect. By comparison, the simple application of a glass cover to a traditional halogen lamp completely prevented genotoxic effects, even after 60 min of exposure at an illuminance of 10,000 lx. Suitable regulations are urgently needed for controlling the biological safety or artificial illumination systems.

Animals↗

PubMedDate not supplied

Effect of bromine and chlorine positioning in the induction of renal and testicular toxicity by halogenated propanes.

A series of halogenated propanes were studied for renal and testicular necrogenic effects in the rat and correlated to their ability to induce in vivo renal and testicular DNA damage and in vitro testicular DNA damage. 1,2-Dibromo-3-chloropropane (DBCP) and 1,2,3-tribromopropane were most potent in causing organ damage in both kidney and testes. Extensive necrosis was evident at 85 mumol/kg in kidney and at 170 mumol/kg in testis. The dibromomonochlorinated analogue 1,3-dibromo-2-chloropropane was less organ toxic than DBCP and 1,2,3-tribromopropane, but induced more organ damage than the dichloromonobrominated analogues 1-bromo-2,3-dichloropropane and 1,3-dichloro-2-bromopropane. Dihalogenated propanes were even less necrogenic. These observed differences in toxic potency between the halogenated propanes could not be explained by relative differences in tissue concentrations. The ability of the halogenated propanes to induce DNA damage in vivo correlated well with their ability to induce organ damage. However, DNA damage occurred at lower doses and at a shorter period of exposure than organ necrosis. This indicates that DNA damage might be an initial event in the development of organ necrosis by halogenated propanes in general. Further, testicular DNA damage induced by the halogenated propanes in vivo correlated well with the DNA damage observed in isolated testicular cells in vitro, showing that toxicity was due to in situ activation. The numbers, positions, and the types of halogen substituents appear to be important determinants in causing DNA damage and necrogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen, equilenin.

Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated equilenin derivatives in vitro, we studied the relative ability of the 17beta-hydroxy-4-halogenated equilenin derivatives to induce estrogenic effects in the ovariectomized rat model. The 4-fluoro derivative showed higher activity than 4-chloro and 4-bromo derivatives as demonstrated by inducing higher vaginal cellular differentiation, uterine growth, and mammary gland branching. However, 17beta-hydroxy-4-fluoroequilenin showed a lower estrogenic activity than 17beta-hydroxyequilenin and estradiol, which could be due to alternative pharmacokinetic properties for these compounds. These data suggest that the 4-fluoroequilenin derivatives have promise as alternatives to traditional estrogen replacement therapy due to their similar estrogenic properties with less overall toxicity.

Adenocarcinoma↗

PubMed2004

The role of vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products.

Halogenated natural products are frequently reported metabolites in marine seaweeds. These compounds span a range from halogenated indoles, terpenes, acetogenins, phenols, etc., to volatile halogenated hydrocarbons that are produced on a very large scale. In many cases these halogenated marine metabolites possess biological activities of pharmacological interest. Given the abundance of halogenated marine natural products found in marine organisms and their potentially important biological activities, the biogenesis of these compounds has intrigued marine natural product chemists for decades. Over a quarter of a century ago, a possible role for haloperoxidase enzymes was first suggested in the biogenesis of certain halogenated marine natural products, although this was long before haloperoxidases were discovered in marine organisms. Since that time, FeHeme- and Vanadium-haloperoxidases (V-HPO) have been discovered in many marine organisms. The structure and catalytic activity of vanadium haloperoxidases is reviewed herein, including the importance of V-HPO-catalyzed bromination and cyclization of terpene substrates.

Biological Products↗