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PubMed2006

Determination of the cryptic stereochemistry of the first PKS chain-extension step in ansamitocin biosynthesis by Actinosynnema pretiosum.

The biosynthesis of the antitumor antibiotic, ansamitocin, involves the assembly of a linear octaketide on the ansamitocin (asm) polyketide synthase (PKS), which is then cyclized to proansamitocin and further modified to the final product. In the first chain-extension step on the asm PKS, a stereocenter is generated which is then obliterated in a subsequent double-bond migration. The cryptic configuration at this stereocenter was determined by first synthesizing the two enantiomers of the intermediate diketide as their N-acetylcysteamine (SNAC) thioesters. These were then used to demonstrate that only the R enantiomer complements a 3-amino-5-hydroxybenzoic acid (AHBA) deficient mutant of Actinosynnema pretiosum to restore ansamitocin formation. The low efficiency of complementation by the diketide, compared to AHBA, is due to inefficient loading onto the PKS and not the inhibition of the enzyme. A presumed next chain-extension intermediate-the triketide with an unrearranged double bond-was also synthesized as its SNAC ester, but did not complement the AHBA(-) mutant.

Actinomycetales↗
PubMed2002

Assignment of absolute configuration of chiral carboxylic acids via exciton-coupled CD treatment: 4-phenylthioproline as a case study.

The 4-hydroxybenzoate chromophore was used as an exciton reporter group for the assignment of the absolute configuration of a chiral carboxylic acid of pharmaceutical interest, (-)-(2S,4S)-4-phenylthioproline, precursor of the ACE-inhibitor zofenopril. The nondegenerate coupling with the preexisting phenylthio chromophore was observed. A detailed conformational analysis, accomplished by means of (1)H-NMR NOESY and semiempirical PM3 computational methods, and quantitative CD calculations were necessary to substantiate the assignment based on a weak experimental couplet.

Journal Article↗
PubMed1996

Variation of the pH of the background electrolyte due to electrode reactions in capillary electrophoresis: theoretical approach and in situ measurement.

Electrode reactions during the electrophoretic process may change the pH of the buffer and subsequently the migration behavior of solutes with resultant loss of reproducibility. A theoretical treatment of pH variations due to electrolytic processes is presented. The choice of buffer appears to have a dramatic influence on the pH variations observed, even if substantial buffer action is expected at the pH chosen. The experimental evaluation of the separation of 4-hydroxy-3-methoxycinnamic acid and 3-hydroxybenzoic acid reveals that the quality of the separation decreases continuously from a baseline separation observed in the first experiment to a comigration of the two solutes (resolution = 0) in the ninth experiment. A pH decrease of about 0.05 pH units accounts for the observed changes in mobility. A novel in situ pH measurement approach is presented, in which the mobility, peak area, and peak height of an indicator dye are related to the pH in the capillary. This enables the identification and quantitation of pH variations during electrophoretic runs: the pH decreases at the anodic side already after the first experiment and pH variations as small as 0.02 pH units can be measured. The variations in peak height appear to be less suited. The calculated pH variations are in close agreement with the ones obtained experimentally.

Buffers↗
PubMed2005

Analyses of phenolic compounds by microemulsion electrokinetic chromatography.

In this study, a microemulsion electrokinetic chromatography (MEEKC) method was developed to analyze and detect 13 phenolic compounds (syringic acid, p-cumaric acid, vanillic acid, caffeic acid, gallic acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, (+)-catechin, (-)-epigallocatechin, (-)-epicatechin gallate, (-)-epigallocatechin gallate, (-)-epicatechin, and (-)-gallocatechin), which are present in many plant-derived foods. The effects of cosurfactant, organic modifier, and oil were examined in order to optimize the separation of these phenolic compounds. The amounts of cosurfactant (cyclohexanol) and organic modifier (acetonitrile) were determined as the major influence on the separation selectivity, while the type of oil partially affected the separation resolution of the phenolic compounds. A highly efficient MEEKC separation method was achieved within 14 min by using a microemulsion solution of pH 2.0 containing 2.89% w/v SDS, 1.36% w/v heptane, 7.66% w/v cyclohexanol, and 2% w/v ACN. Furthermore, the present work could demonstrate that the nature of the oil phase has a significant influence on the separation selectivity of phenolic compounds.

Acetonitriles↗
PubMed1992

Mutagenicity of benzo(a)pyrenyl-1-sulfate in the Ames test.

Comparison of the mutagenicity of nine isomeric benzo(a)pyrenyl [B(a)P] phenols conjugated with either sulfate or glucuronide was carried out using strain Salmonella typhimurium TA98. Of the nine conjugates tested, only B(a)P-1-sulfate was mutagenic. Accordingly, the mutagenicity of B(a)P-1-sulfate was compared with that of B(a)P and 1-hydroxybenzo(a)pyrene [B(a)P-1-OH] in the presence and absence of rat lung S9 and Aroclor-induced liver S9 with and without an NADPH-generating system. B(a)P-1-sulfate was slightly mutagenic, whereas B(a)P and the 1-hydroxy derivative were nonmutagenic when S9 fractions and NADPH were omitted. Addition of induced liver S9 with NADPH caused mutagenicity with B(a) -1-OH greater than B(a)P greater than B(a)P-1-sulfate. B(a)P-1-sulfate was the only mutagenic species when lung S9 was added. This mutagenicity did not require NADPH. Sodium sulfite, an inhibitor of arylsulfatase, decreased the mutagenicity of B(a)P-1-sulfate. These data suggest that a unique mutagenic species is generated from B(a)P-1-sulfate via arylsulfatase in rat lung.

Animals↗
PubMed1983

Rat nasal tissue activation of benzo(a)pyrene and 2-aminoanthracene to mutagens in Salmonella typhimurium.

Cytochrome P-450-dependent monooxygenase activity has been measured in the nasal turbinates of dogs and rats. The capacity of male Fischer-344 rat nasal tissue to bioactivate benzo(a)pyrene (BaP) and 2-aminoanthracene (2-AA) to mutagens in Salmonella typhimurium was investigated. 2-AA was mutagenic in strains TA98 and TA100 when nasal tissue S-9 was utilized as the activating enzyme system and BaP was mutagenic in strain TA100. At all doses and protein concentrations tested, 2-AA displayed nearly 500-1000 times greater bacterial mutagenicity than BaP. In strain TA-100, nasal tissue S-9 was approximately twice as active toward 2-AA as lung S-9 and 75% as active as liver S-9. Aryl hydrocarbon hydroxylase activity was detected in rat nasal tissue when 14C-BaP was used as a substrate. Rat nasal tissue metabolized BaP to several oxidized metabolites which included dihydrodiols, quinones, and phenols. 3-Hydroxybenzo(a)pyrene and BaP-3, 6-quinone were the major metabolites detected (150 pmoles/mg protein/30 min). These results indicate that rat nasal tissue can metabolize promutagens to reactive species which may play an important role in xenobiotic-induced nasal tumors.

Animals↗
PubMed1975

Retention of tritium during the binding of tritiated benz(a)pyrene to DNA.

Chemical conversion of generally tritiated benzo(a)pyrene to 6 and 1,6-substituted derivatives resulted in 30% and 48% loss of tritium respectively. Metabolism of [3H], [14C]-benzo(a)pyrene by rat liver microsomes yielded 3-hydroxybenzo(a)pyrene with 30% loss of tritium, a mixture of quinones with 50% loss of tritium and three dihydrodiol metabolites which had retained all the tritium of the parent hydrocarbon. DNA isolated from mouse embryo cells which had been exposed to [3H], [14C]-benzo(a)pyrene, and DNA with this hydrocarbon bound following in vitro rat liver microsomal incubation were degraded enzymically and the hydrocarbon-deoxyribonucleoside products isolated. The tritium contents of the products obtained from both DNA samples were very close to those of the original double labelled benzo(a)pyrene. These results are inconsistent with a phenol or quinone intermediate being responsible for the reaction with DNA, but fully consistent with a diol epoxide intermediate as proposed by Sims et al. (1974).

Animals↗
PubMedDate not supplied

Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells.

Since the alkyl esters of p-hydroxybenzoic acid (parabens) can be measured intact in the human breast and possess oestrogenic properties, it has been suggested that they could contribute to an aberrant burden of oestrogen signalling in the human breast and so play a role in the rising incidence of breast cancer. However, although parabens have been shown to regulate a few single genes (reporter genes, pS2, progesterone receptor) in a manner similar to that of 17beta-oestradiol, the question remains as to the full extent of the similarity in the overall gene profile induced in response to parabens compared with 17beta-oestradiol. The GE-Amersham CodeLink 20 K human expression microarray system was used to profile the expression of 19881 genes in MCF7 human breast cancer cells following a 7-day exposure to 5 x 10(-4) M methylparaben, 10(-5) M n-butylparaben and 10(-8) M 17beta-oestradiol. At these concentrations, the parabens gave growth responses in MCF7 cells of similar magnitude to 17beta-oestradiol. The study identified genes which are upregulated or downregulated to a similar extent by methylparaben, n-butylparaben and 17beta-oestradiol. However, the majority of genes were not regulated in the same way by all three treatments. Some genes responded differently to parabens from 17beta-oestradiol, and furthermore, differences in expression of some genes could be detected even between the two individual parabens. Therefore, although parabens possess oestrogenic properties, their mimicry in terms of global gene expression patterns is not perfect and differences in gene expression profiles could result in consequences to the cells that are not identical to those following exposure to 17beta-oestradiol.

Breast Neoplasms↗
PubMedDate not supplied

Oestrogenic activity of isobutylparaben in vitro and in vivo.

The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in foods, pharmaceuticals and cosmetics to which the human population is exposed. Recent studies have reported that methylparaben, ethylparaben, n-propylparaben and n-butylparaben all possess oestrogenic activity in several in vitro assays and in animal models in vivo. This study reports on the oestrogenic activity of isobutylparaben in a panel of assays in vitro and in vivo. Isobutylparaben was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor alpha of MCF7 human breast cancer cells by 81% at 100 000-fold molar excess. Using a clonal line of MCF7 cells containing a stably transfected oestrogen-responsive ERE-CAT reporter gene, CAT gene expression could be increased by isobutylparaben such that the magnitude of the response was the same at 10(-5) M isobutylparaben as with 10(-8) M 17beta-oestradiol. Isobutylparaben could also increase expression of the endogenous oestrogen-responsive pS2 gene in MCF7 cells and maximal expression at 10(-5) M isobutylparaben could be inhibited with the anti-oestrogen ICI 182 780. The proliferation of two oestrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1 could be increased with isobutylparaben such that at concentrations of 10(-5) M the proliferation response was of the same magnitude as with 10(-8) M 17beta-oestradiol. Evidence for oestrogen receptor mediation of proliferation effects was provided by the inability of isobutylparaben to influence the growth of oestrogen-unresponsive MDA-MB-231 human breast cancer cells and by the ability of the anti-oestrogen ICI 182 780 to inhibit the isobutylparaben effects on MCF7 cell growth. The proliferation response to 10(-10) M 17beta-oestradiol was not antagonized with isobutylparaben at any concentration from 10(-9) M to 10(-4) M in either MCF7 or ZR-75-1 cells. Finally, subcutaneous administration of isobutylparaben was able to increase the uterine weight in the immature mouse after three daily doses of 1.2 or 12.0 mg per mouse. Previous work using linear-alkyl-chain parabens has shown that oestrogenic activity increases with alkyl chain length from methylparaben to n-butylparaben. The results here show that branching of the alkyl chain to isobutylparaben increases oestrogenic activity beyond that of the equivalent length linear alkyl chain in n-butylparaben.

Animals↗
PubMedDate not supplied

Oestrogenic activity of benzylparaben.

Previous work has demonstrated that the alkyl esters of p-hydroxybenzoic acid (parabens) possess oestrogenic activity, which increases with length of alkyl chain from methylparaben to n-butylparaben and with branching in the alkyl chain from n-butylparaben to isobutylparaben. This study reports on the oestrogenic activity of benzylparaben in a variety of assays in vitro and in vivo. Benzylparaben was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor (ER) of MCF7 human breast cancer cells by 22% at 1000-fold molar excess, by 40% at 10,000-fold molar excess, by 57% at 100 000-fold molar excess and by 100% at 1,000,000-fold molar excess. It was able to increase expression of a stably transfected oestrogen responsive reporter gene (ERE-CAT) in MCF7 cells after 24 h at 10(-5)M/10(-4)M and after 7 days at 10(-6)M/10(-5)M/10(-4)M. Proliferation of MCF7 cells could be increased by 10(-6)M/10(-5)M benzylparaben and this could be inhibited by 10(-7)M pure anti-oestrogen ICI 182,780, indicating that growth effects were ER mediated. Further evidence for ER-mediation was provided from the ability of benzylparaben to increase the growth of a second oestrogen-dependent human breast cancer cell line ZR-75-1, but not the oestrogen-insensitive MDA-MB-231 cell line. When tested in the presence of 10(-10)M 17beta-oestradiol, benzylparaben gave no antagonist response on the growth of either MCF7 or ZR-75-1 cells. Finally, benzylparaben could increase uterine weight in the immature mouse following topical application of three daily doses of 33 mg to dorsal skin. These results demonstrate that the oestrogenicity of methylparaben can be increased by the addition of an aryl group as well as by lengthening or branching the alkyl grouping.

Administration, Topical↗
PubMedDate not supplied

Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis.

A recent review by Darbre (2003) published in this journal (J. Appi. Toxicol. 23: 89-95) has attracted public and scientific interest that requires perspective, particularly on the use of esters of p-hydroxybenzoic acid (parabens) as preservatives in underarm cosmetics. Although parabens are generally regarded as safe, recent reports suggest that they are oestrogenic in a variety of in vitro (including MCF7 and ZR-75-1 human breast cancer cell lines) and in vivo tests for oestrogenicity (uterotrophic assays in both rat and mouse). There are also recent reports of adverse reproductive and developmental outcomes in rodent toxicity studies. Of interest is the lack of activity by the oral route but clear activity by the subcutaneous and topical routes, which is of some relevance to the use of underarm cosmetics. There would seem to be a case now to supplement these emerging toxicity data with longer term regulatory standard tests examining other oestrogenic endpoints and at least to consider these findings in more up-to-date risk assessments specific for cosmetic use. Further, there are few data on the use of underarm cosmetics and the risk of breast cancer, and although one recent retrospective interview-based study found no association there is a need for more thorough investigation taking into account the type of chemicals used. Darbre has forwarded a hypothesis and called for further work to establish whether or not the use of underarm cosmetics (particularly containing oestrogenic formulants) contributes to the rising incidence of breast cancer. It would seem prudent to conduct this work because the current database is sparse and the effects of long-term low-level exposures to weakly oestrogenic chemicals on human health, particularly their application to the underarm and the risks of breast cancer, are unknown. The role of oestrogens in breast cancer, however, is undisputed.

Animals↗
PubMedDate not supplied

Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women?

In the decade that has elapsed since the suggestion that exposure of the foetal/developing male to environmental oestrogens could be the cause of subsequent reproductive and developmental effects in men, there has been little definitive research to provide conclusions to the hypothesis. Issues of exposure and low potency of environmental oestrogens may have reduced concerns. However, the hypothesis that chemicals applied in body care cosmetics (including moisturizers, creams, sprays or lotions applied to axilla or chest or breast areas) may be affecting breast cancer incidence in women presents a different case scenario, not least in the consideration of the exposure issues. The specific cosmetic type is not relevant but the chemical ingredients in the formulations and the application to the skin is important. The most common group of body care cosmetic formulation excipients, namely p-hydroxybenzoic acid esters or parabens, have been shown recently to be oestrogenic in vitro and in vivo and now have been detected in human breast tumour tissue, indicating absorption (route and causal associations have yet to be confirmed). The hypothesis for a link between oestrogenic ingredients in underarm and body care cosmetics and breast cancer is forwarded and reviewed here in terms of: data on exposure to body care cosmetics and parabens, including dermal absorption; paraben oestrogenicity; the role of oestrogen in breast cancer; detection of parabens in breast tumours; recent epidemiology studies of underarm cosmetics use and breast cancer; the toxicology database; the current regulatory status of parabens and regulatory toxicology data uncertainties. Notwithstanding the major public health issue of the causes of the rising incidence of breast cancer in women, this call for further research may provide the first evidence that environmental factors may be adversely affecting human health by endocrine disruption, because exposure to oestrogenic chemicals through application of body care products (unlike diffuse environmental chemical exposures) should be amenable to evaluation, quantification and control. The exposure issues are clear and the exposed population is large, and these factors should provide the necessary impetus to investigate this potential issue of public health.

Breast Neoplasms↗
PubMed1990

Diethylstilbestrol potentiates and testosterone antagonizes the action of 3-methylcholanthrene on benzo(a)pyrene metabolism in Hep G2 cells.

We have used the human hepatoma cell line, Hep G2, to examine the ability of hormones and xenobiotics to modulate the hepatic induction of benzo(a)pyrene hydroxylase and epoxide hydrolase. Hep G2 cells were cultured in Eagle's Minimum Essential Medium supplemented with 10% fetal calf serum. 3-Methylcholanthrene, diethylstilbestrol, testosterone propionate, and combinations of 3-methylcholanthrene, and each of the hormones were added directly to the culture media. We subsequently studied the metabolism of benzo(a)pyrene using cell lysates of the Hep G2 cells. Metabolites were quantitated by high-performance liquid chromatography (HPLC) using fluorodetection. Exposure to 3-methylcholanthrene alone resulted in an eightfold increase in total benzo(a)pyrene metabolites with a change of the predominant metabolite from the 3-hydroxybenzo(a)pyrene to the carcinogenic pathway of the benzo(a)pyrene-7,8-diol. Diethylstilbestrol and testosterone propionate resulted in small, but significant, decreases in metabolism of benzo(a)pyrene. When exposed in combination with 3-methylcholanthrene, testosterone propionate antagonized and diethylstilbestrol potentiated the metabolism of benzo(a)pyrene. 3-Methylcholanthrene, diethylstilbestrol, and combinations of 3-methylcholanthrene and diethylstilbestrol or testosterone propionate resulted in increased epoxide hydrolase activity as compared to controls. These results, carried out in a human hepatoma cell line, lend support to a concern for potentiated toxicity and carcinogenicity following exposure to complex chemical mixtures.

Benzo(a)pyrene↗
PubMed1993

Utilization of aromatic compounds by the Penicillium strain Bi 7/2.

The Penicillium strain Bi 7/2 utilized phenol, catechol, resorcinol, hydroquinone, pyrogallol, hydroxyhydroquinone, phloroglucinol, m- and p-cresol, orcinol, 4-methylcatechol, 4-methoxyphenol, 4-aminophenol, benzyl alcohol, benzoic acid, 2-, 3- and 4-hydroxybenzoic acid, anthranilic acid, protocatechuic acid and gallic acid as sole sources of carbon and energy. The central metabolites catechol, protocatechuic acid and hydroxyquinone could be determined by HPLC with diode-array detection. Pathways for the degradation of aromatic substances were proposed.

Biodegradation, Environmental↗
PubMed1995

Cometabolic degradation of o-cresol and 2,6-dimethylphenol by Penicillium frequentans Bi 7/2.

o-Cresol induced glucose-grown resting mycelia of Penicillium frequentans Bi 7/2 (ATCC-number: 96048) immediately oxidized o-cresol and other phenols. After precultivation on glucose and phenol degradation started after a lag-phase of 24 hours. Metabolites of o-cresol metabolism were methylhydroquinone, methyl-p-benzoquinone, 2-methyl-5-hydroxyhydroquinone and 2-methyl-5-hydroxy-p-benzoquinone. The initial reaction is probably catalyzed by a NADPH dependent hydroxylase which is specific for o-cresol. The metabolism of 2,6-dimethylphenol (2,6-xylenol) occurred via 2,6-dimethylhydroquinone, 2,6-dimethyl-p-benzoquinone, 2,6-dimethyl-3-hydroxyhydroquinone, 2,6-dimethyl-3-hydroxy-p-benzoquinone and 3-methyl-2-hydroxybenzoic acid.

Chromatography, High Pressure Liquid↗
PubMed2006

Polymorphism and pseudopolymorphism of salicaine and salicaine hydrochloride crystal polymorphism of local anaesthetic drugs, part V.

The local anaesthetic drug salicaine hydrochloride (hydroxytetracaine hydrochloride, 4-butylamino-2-hydroxybenzoic acid 2-dimethylaminoethyl ester hydrochloride, SLCHC) and the free-base salicaine (SLC) were characterized by thermal analysis, vibrational and solid-state NMR-spectroscopy, X-ray powder diffraction, X-ray single crystal structure analysis, and water vapor sorption analysis. Additionally, the crystal structures of the anhydrate mod. II degrees (monoclinic, space group P2(1)/n), the hydrated mod. I (triclinic, space group P(bar)1), and of the free base (SLC) in the form of the hemihydrate (triclinic, space group P(bar)1 are discussed. Mod. II degrees of the polymorphic SLCHC is the thermodynamically stable form at room temperature and is present in commercial products mostly contaminated with a hydrated form that is isomorphic with mod. I. Mod. II degrees crystallizes from most organic solvents and from the melt below 110 degrees C. Mod. I crystallizes from the melt at temperatures above 110 degrees C, and additionally appears on dehydration of the hydrated mod. I. A third polymorph monotropically related to mod. II degrees was found by freeze-drying. The free-base SLC was found to crystallize from ethanol/water as a triclinic hemihydrate.

Absorption↗
PubMed1976

Molecular orbital calculations for parabens: a possible mechanism of action.

Molecular orbital calculations were carried out on the series benzoic acid, p-hydroxybenzoic acid, methylparaben, and ethylparaben. The characteristic trends of this entire series of preservatives are demonstrated by these members. The computer program used was Iterated Extended Hückel Theory. These systems were characterized in terms of atomic charge distributions, effect of hydroxyl and ester groups (both sterically and electronically), preferred molecular conformations, and distinguishing features of molecular orbitals. Through this approach, it was hoped that a common mode of action for all members of this series could be detected and that the trend(s) in this feature would correlate with known trends in activity of members of this series.

Chemical Phenomena↗
PubMed1977

Solubility profiles and thermodynamics of parabens in aliphatic alcohols.

The solubility of a series of compounds was determined in a wide polarity spectrum of normal aliphatic alcohols over a limited temperature range. The solutes chosen were the methyl through n-butyl p-hydroxybenzoates, several of these being useful preservatives. Solubility profiles were determined for these compounds, and the effect of temperature upon their solubility behavior was investigated. The solubility of the solutes is expressed in several concentration notations; mole fraction plots showed a variable twin peak array as a function of the dielectric constant for the solutes studied. Since heats of fusion were available and data were generated as a function of temperature, thermodynamic parameters for these systems could be calculated. The relationship of these parameters to multiple solubility peak array is discussed.

Alcohols↗