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PubMed2004

A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis.

The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI(50)) of 0.04 nM and a maximum inhibition of >95% at 1 nM. Human umbilical vein endothelial cells (HUVEC) are similarly inhibited in proliferation by PPI-2458 (GI(50), 0.2 nM). We developed a method to measure the level of MetAP-2 enzyme inhibition after exposure to PPI-2458 and demonstrate that growth inhibition of PPI-2458-sensitive HFLS-RA and HUVEC is linked to MetAP-2 enzyme inhibition, in a dose-dependent fashion. The secretion of several inflammatory mediators such as IL-6 and vascular endothelial growth factor from activated HFLS-RA was not inhibited by PPI-2458. The CNS toxicity profile of PPI-2458, determined by the incidence of seizures, is significantly improved over that of the parental compound TNP-470. In the rat model of peptidoglycan-polysaccharide-induced arthritis, PPI-2458 significantly attenuated paw swelling when therapeutically administered after the onset of chronic disease. We suggest that the mechanism of PPI-2458 action, highly selective and potent anti-proliferative activity on HFLS-RA and HUVEC in vitro, a significantly improved CNS toxicity profile, and marked attenuation of chronic disease in the rat peptidoglycan-polysaccharide arthritis model in vivo, positions this compound as a drug for the treatment of RA.

Aminopeptidases↗
PubMed1976

Epoxide to olefin: a novel biotransformation in the rumen.

Studies with an insect juvenile hormone mimic and the insecticide dieldrin have shown that enzymatic processes in the rumen reduce the epoxide moiety in these compounds to an olefin. This reaction is apparently microbial in origin and does not involve an observable intermediate. Epoxide reductions in the digestive tract of ruminants and possibly other mammals may be important in the detoxication of biologically active epoxides, including pesticides, alkylating agents, and carcinogens.

Animals↗
PubMed1994

Biotransformation and toxicity of halogenated benzenes.

1. Multiple potentially harmful metabolites can be distinguished in the metabolic activation of halogenated benzenes: epoxides, phenols, benzoquinones and benzoquinone-derived glutathione conjugates. 2. The role of these (re-) active metabolites in the toxic effects induced by halogenated benzenes such as hepatotoxicity, nephrotoxicity, porphyria and thyroid toxicity is discussed. 3. Evidence is presented suggesting that the formation of reactive benzoquinone metabolites rather than the traditional epoxides is linked to halogenated benzene-induced hepatotoxicity. 4. A crucial role for the benzoquinone-derived glutathione adducts in halogenated benzene-induced nephrotoxicity is clearly established. 5. Although metabolic activation appears to be involved in porphyria, the nature of the ultimate porphyrinogenic metabolite has not been elucidated yet. 6. Disturbances in thyroid hormone (and retinoid) homeostasis can be (at least partially) explained by the formation of halogenated phenol metabolites. 7. In conclusion, for a relevant prediction of the ultimate fate of a compound in a living organism, one should know the chemical characteristics and reactivity of the parent compound and its metabolites, together with insight into the formation mechanism of each of the suspected metabolites, and an understanding of the interaction between a specific chemical (reactive) structure and its target molecule.

Animals↗
PubMed1995

New metabolites with nematicidal and antimicrobial activities from the ascomycete Lachnum papyraceum (Karst.) Karst. VII. Structure determination of brominated lachnumon and mycorrhizin A derivatives.

The structure determination of lachnumon B1 (16) and lachnumon B2 (17), brominated derivatives of lachnumon (1), as well as mycorrhizin B1 (18) and mycorrhizin B2 (19), brominated derivatives of mycorrhizin A (3), is described. The compounds, which exhibit similar antimicrobial and nematicidal activity as their chlorinated analogues, were isolated from extracts of cultures of the ascomycete Lachnum papyraceum to which CaBr2 had been added. The structures were elucidated by spectroscopic methods.

Anti-Bacterial Agents↗
PubMed2006

Comparison of styrene and its metabolites styrene oxide and 4-vinylphenol on cytotoxicity and glutathione depletion in Clara cells of mice and rats.

Styrene is a widely used compound in the manufacturing industry. In mice and rats, it is both hepatotoxic and pneumotoxic. It causes lung tumors in mice, but not in rats. The Clara cell is the main target for the toxicity of styrene and its metabolites, and it also has the greatest activity for styrene metabolism. Therefore, Clara cells isolated from CD-1 mice and Sprague-Dawley rats were used to compare the cytotoxicities induced by styrene and its metabolites. The cytotoxicity of styrene was greater in vitro than that of its metabolites styrene oxide (racemic, R- and S-) and 4-vinylphenol in contrast with what has been observed in vivo in previous studies on hepatotoxicity and pneumotoxicity. Susceptibility of rats to styrene and its metabolites are 4-fold less than that observed with mice. Glutathione levels were also measured in mice following addition of the chemicals in vitro and treatment of the CD-1 mice in vivo. Decreases in glutathione concentrations were seen even at doses which did not cause the death of mouse Clara cells. Significant decreases in glutathione were observed 3h after treatment with racemic SO and R-SO. At 12h, rebound effects were seen for all compounds, with all but R-SO rebounding above controls. These studies suggest that in vitro cytotoxicity of styrene and its metabolites does not strictly follow in vivo effects and that decreases in mouse glutathione levels may be related to oxidative stress.

Animals↗
PubMed2002

DNA damage and repair in human leukocytes exposed to styrene-7,8-oxide measured by the comet assay.

Styrene-7,8-oxide (SO) is produced by cytochrome p450 monooxygenases as the main mammalian metabolite of styrene, an important industrial chemical present at high concentrations in the ambient air of fiberglass-reinforced plastic plants. Previous studies have shown positive results for SO in the induction of several cytogenetic endpoints in vitro. In this work we have evaluated, by means of the comet assay, the potential of SO to act as a DNA damaging agent in human peripheral leukocytes and the ability of white blood cells to repair the DNA damage induced by this compound. Our results show that SO induces DNA damage at concentrations higher than 50 microM in a dose-dependent manner, and that the lesions produced by SO are efficiently removed within a few hours after the end of treatment.

Adult↗
PubMed1999

PG490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells.

Progress in the treatment of solid tumors has been slow and sporadic. The efficacy of conventional chemotherapy in solid tumors is limited because tumors frequently have mutations in the p53 gene. Also, chemotherapy only kills rapidly dividing cells. Members of the tumor necrosis factor (TNF) family, however, induce apoptosis regardless of the p53 phenotype. Unfortunately, the cytotoxicity of TNF-alpha is limited by its activation of NF-kappaB and activation of NF-kappaB is proinflammatory. We have identified a compound called PG490, that is composed of purified triptolide, which induces apoptosis in tumor cells and sensitizes tumor cells to TNF-alpha-induced apoptosis. PG490 potently inhibited TNF-alpha-induced activation of NF-kappaB. PG490 also blocked TNF-alpha-mediated induction of c-IAP2 (hiap-1) and c-IAP1 (hiap-2), members of the inhibitor of apoptosis (IAP) family. Interestingly, PG490 did not block DNA binding of NF-kappaB, but it blocked transactivation of NF-kappaB. Our identification of a compound that blocks TNF-alpha-induced activation of NF-kappaB may enhance the cytotoxicity of TNF-alpha on tumors in vivo and limit its proinflammatory effects.

Antineoplastic Agents, Alkylating↗
PubMed1985

Decrease of fatty acid oxidation, ketogenesis and gluconeogenesis in isolated perfused rat liver by phenylalkyl oxirane carboxylate (B 807-27) due to inhibition of CPT I (EC 2.3.1.21).

Sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27 or POCA) inhibits ketogenesis from endogenous and exogenous long-chain fatty acids and 14CO2 production from [U-14 C]palmitate, but not from [U-14 C]palmitoylcarnitine or octanoate, and inhibits gluconeogenesis from lactate and pyruvate in perfused livers of starved rats. Inhibition of ketogenesis, 14CO2 production and gluconeogenesis was complete at concentrations of 10 mumol/l POCA, but onset was more rapid for inhibition of ketogenesis and CO2 production than for gluconeogenesis. Infusion of octanoate abolished inhibition of all three processes. Experiments with isolated rat liver mitochondria showed that carnitine palmitoyltransferase I (EC 2.3.1.21) is inhibited by POCA-CoA. The inhibitory process is dependent on time and concentration, and more pronounced in mitochondria from fed than from fasted rats. Concentrations required for 50% inhibition after 20 min preincubation with POCA-CoA are 0.02, 0.06 and 0.1 mumol/l in liver mitochondria from fed, 24-h-fasted and 48-h-fasted rats, respectively. The inhibitor appears to be tightly bound to the enzyme. The extent of inhibition of carnitine palmitoyltransferase I correlates well with the hypoglycaemic and hypoketonaemic effects of the compounds in fasted rats. We conclude that specific inhibition of the enzyme leads, due to inhibition of long-chain fatty acid utilization, to depressed ketogenesis and gluconeogenesis and, in consequence, to hypoglycaemic and hypoketonaemia in vivo under gluconeogenic and ketogenic conditions.

Animals↗
PubMed1993

MS-347a, a new inhibitor of myosin light chain kinase from Aspergillus sp. KY52178.

MS-347a was isolated from the culture broths of Aspergillus sp. KY52178 as an inhibitor of smooth muscle myosin light chain kinase (MLCK). MS-347a inhibited the activity of chicken gizzard MLCK with an IC50 value of 9.2 microM. The inhibition was dependent on time of preincubation of MS-347a with the enzyme, suggesting irreversible inhibition. It is likely that the inhibitor binds to the catalytic domain of MLCK, since the compound inhibited not only calmodulin-dependent but also calmodulin-independent activity of MLCK. Calmodulin-dependent cyclic nucleotide phosphodiesterase, cAMP-dependent protein kinase and cGMP-dependent protein kinase were not inhibited by 150 microM MS-347a at all, although the compound inhibited protein kinase C with an IC50 value of 16 microM. MS-347b, a minor component was also isolated from the same culture broths. This minor component at 150 microM did not inhibit the activity of MLCK.

Aspergillus↗
PubMedDate not supplied

Overall migration and specific migration of bisphenol A diglycidyl ether monomer and m-xylylenediamine hardener from an optimized epoxy-amine formulation into water-based food simulants.

The overall and specific migrations of BADGE n = 0 monomer and m-XDA hardener from a BEPOX LAB 889 (Gairesa internal code), epoxy system cured at room temperature, into three water-based food simulants are studied. Hydrolysis of BADGE n = 0 was observed in all of these simulants, giving more polar products. We thus propose changing the EEC Directives, which at present only legislate for levels of BADGE n = 0 monomer in the simulants, to include the hydrolysis products of BADGE monomers. Another alternative would be to express all the migration levels due to BADGE and its derived products in terms of BADGE itself.

Benzhydryl Compounds↗
PubMed1983

Differential induction of cytosolic epoxide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities.

Three major enzyme systems have been shown to metabolize epoxidized xenobiotics in vertebrate tissues, and this study demonstrates that these enzyme systems can be differentially induced. The cytosolic epoxide hydrolase activity was routinely monitored with trans-beta-ethylstyrene oxide, the microsomal epoxide hydrolase activity with benzo(a)pyrene, 4,5-oxide, and the glutathione S-transferase activity with 2,4-dichloro-4-nitrobenzene. Commonly used inducers of microsomal mixed-function oxidase, microsomal epoxide hydrolase, and cytosolic glutathione S-transferase activities failed to cause significant induction of the cytosolic epoxide hydrolase while leading to the expected induction of the other epoxide metabolizing enzymes. The compounds tested by ip injection into male Swiss-Webster mice included phenobarbital, 3-methylcholanthrene, Aroclor 1254, trans- and cis-stilbene oxides, pregnenolone-16 alpha-carbonitrile, chalcone, and 4-bromochalcone. To determine if there were strain, sex, or species differences, the enzymes were monitored in male C57BL/6 mice, female Swiss-Webster mice, and male Sprague-Dawley rats following ip injection of phenobarbital, 3-methylcholanthrene, and/or pregnenolone-16 alpha-carbonitrile. The time dependence of enzyme induction was followed in Sprague-Dawley rats following trans-stilbene oxide administration. Male Swiss-Webster mice were additionally exposed to dietary alpha-naphthoflavone and 2(3)-tert-butyl-4-hydroxyanisole while male Sprague-Dawley rats were fed 2,6-di-tert-butyl-4-methylphenol. In no case was significant induction of cytosolic epoxide hydrolase activity observed. Dietary di-(2-ethylhexyl)phthalate, 2-ethyl-l-hexanol, and clofibrate proved to be potent inducers of the cytosolic epoxide hydrolase in male Swiss-Webster mice while probucol (a nonperoxisome proliferating hypolipidemic drug) failed to cause significant induction. Data from isoelectric focusing experiments and other data are consistent with the epoxide hydrolase activities induced by 2-ethyl-l-hexanol and clofibrate being due to the same protein that is present in control animals. The lack of induction of the cytosolic epoxide hydrolase by a variety of compounds which were selected to demonstrate induction of other xenobiotic metabolizing enzymes, may indicate that the cytosolic epoxide hydrolase has a constitutive role whereas its induction by clofibrate could be related to some of the pharmacological and/or carcinogenic actions of this drug.

Animals↗
PubMed1999

Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements.

Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity. Compound 9a was found to have moderate in vivo bioavailability.

3T3 Cells↗
PubMed2005

Styrene monomer primarily induces CYP2B1 mRNA in rat liver.

To determine the cytochrome P450 (CYP) primarily expressed after styrene exposure, seven forms of hepatic CYP mRNA in rats treated with 600 mg kg(-1) styrene were examined. CYP1A2, CYP2B1/2, CYP2E1 and CYP3A2 mRNA were observed using real-time LightCycler PCR. The amount of CYP2B1 mRNA was significantly increased, 47-fold compared with controls, suggesting that this CYP is the primary cytochrome P450 in rats exposed to styrene. Significant increases in the amount of CYP2E1, CYP1A2 and CYP2B2 mRNA were also observed after styrene exposure, and their increase levels were 3.1-, 1.7- and 1.7-fold higher than controls, respectively. Western blot analysis also indicated that the protein levels of CYP2B1, CYP2B2, CYP2E1 and CYP1A2 showed clear increases after styrene treatment, corresponding to their mRNA expression. CYP2C11 mRNA decreased significantly in rats after styrene exposure. CYP1A1 was detected at the mRNA level in rat liver, but it was not detected at the protein level. The expression of epoxide hydrolase (EH), involved in Phase I drug metabolism, was also examined. EH mRNA increased 2-fold compared with controls after styrene exposure. Styrene thus appears to be a chemical compound that induces multiple CYPs. The results demonstrate that CYP2B1 is the primarily induced CYP form by styrene treatment to rats at acute toxic level.

Animals↗
PubMedDate not supplied

Toxic agents resulting from the oxidative metabolism of steroid hormones and drugs.

The oxidative metabolism of some exogenous compounds, and possibly some endogenous compounds as well, can lead to the formation of reactive metabolites. These intermediates react as electrophiles, and they lead in some instances to cell death or cell transformation. Three routes (other routes are also known) of toxicity are discussed. These are the epoxide/dihydrodiol pathway, the catechol/o-quinone pathway, and the alkylation pathway. The possible formation of electrophiles from diethylstilbestrol, from natural estrogens, and from ethynylestradiol is discussed in terms of protein binding. Protein binding is presumptive evidence of electrophile formation, but it does not necessarily indicate that the parent compound is highly cytotoxic, mutagenic, or carcinogenic. Mutagenic and carcinogenic activity is presumed to require reaction of an electrophile with nuclear material. There is evidence for protein binding for these estrogens (diethylstilbestrol, natural estrogens, ethnylestradiol) as a consequence of oxidative metabolism.

Alkylation↗
PubMed1986

Electrofluorescence study of polycyclic hydrocarbon diol-epoxide binding to DNA.

By the use of a novel electrofluorescence method, estimates have been made of the geometry of binding to DNA of racemic mixtures of the anti-diol-epoxide derivatives of three polycyclic hydrocarbon carcinogens. These anti-configurations bind in a manner consistent with the planar diol-epoxide ring's being inclined at approximately 50 degrees to the DNA axis. This is true for the derivatives of benzo(a)pyrene, benz(a)anthracene and 3-methylcholanthrene. This binding is thus different from the regular intercalative interaction associated with the native hydrocarbons. As the (+ anti)-diol-epoxides are thought to be the initiatory compounds for carcinogenesis, the common binding characteristics for the three hydrocarbons may be significant in understanding the molecular interactions precursive to cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2005

[Pharmacologic intervention for vascular calcification].

In patients with chronic renal insufficiency and dialysis, phosphate retention is a major factor in the development of vascular calcification. Prevention of phosphate retention with dietary and pharmacological means may prevent vascular calcification. Current therapy for hyperphosphatemia includes the administration of phosphate binders such as calcium carbonate (or calcium acetate), ammonium-based compounds, and phosphate-binding polymers (Renagel; sevelamer hydrochloride). However, it is difficult to administrate present phosphate binders to patients because of hypocalcaemia, outright toxicity, and constipation as its side effect. It is needed to development new drugs having fewer side effects and better compliance.

Calcinosis↗
PubMed2006

Determination of polyunsaturated fatty acid monoepoxides by high performance liquid chromatography-mass spectrometry.

Despite the implication of polyunsaturated fatty acid monoepoxides in a large panel of biological effects, few methods allowing their separation in a single run are available. We describe here a simple method based on reversed-phase ion-pair high-performance liquid chromatography (RP-HPLC) and developed to successfully separate the various monoepoxides of eicosatrienoic, arachidonic, eicosapentaenoic and docosahexaenoic acids. These compounds were easily identified by liquid chromatography-mass spectrometry (LC-MS) with atmospheric pressure chemical ionisation owing to the volatility of counter-ion species. Compared to established methods, this new protocol proved its ability to totally resolve, in a single run, all of the different regioisomeric epoxides. In the long run, this method will demonstrate its efficacy to give insights into the cytochrome P450-dependent metabolism of polyunsaturated fatty acids (PUFAs) and the generation of physiologically active epoxy-derivatives.

Aryl Hydrocarbon Hydroxylases↗