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PubMed2001

Preliminary assessment of the skin sensitizing activity of selected rodent carcinogens using the local lymph node assay.

It has been demonstrated previously that there exists an incomplete correlation between the skin sensitizing potential of chemicals and their mutagenic properties as judged by activity in the Salmonella mutation assay. More recently, it has been proposed that there may exist a broader association between carcinogenicity in rodents (including non-genotoxic carcinogenesis) and skin sensitizing activity. To explore further these putative relationships we have here examined the skin sensitizing potential of two non-genotoxic rodent carcinogens which are generally considered not to represent a carcinogenic hazard in humans (limonene and saccharin) and of three genotoxic rodent carcinogens (vinylidene dichloride, ethyl acrylate and bisphenol A diglycidyl ether). For this purpose we have used the local lymph node assay (LLNA), a method for the identification and characterization of skin sensitizing chemicals that has recently been recognized as a stand-alone method for hazard identification purposes. Activity in the LLNA was compared with the results of Salmonella tests conducted previously. This small series of investigations reveals that there exists no general relationship between skin sensitizing potential and rodent carcinogenicity. Furthermore, although a general correlation does exist between mutagenic activity and skin sensitization, this association is not universal and activity in the Salmonella mutation assay does not necessarily imply skin sensitizing potential. Collectively these data suggest that it is inappropriate currently to recommend the use of skin sensitization tests as an adjunct to conventional approaches to the evaluation of potential carcinogenicity.

Acetates↗
PubMed2003

Potassium channel activators based on the benzopyran substructure: synthesis and activity of the C-8 substituent.

The synthesis of a series of methoxy bearing 2,2-dimethyl-2H-1-benzopyrans have been achieved for testing as potassium channel activators. The synthesis involves formation of 6-cyano-8-methoxy-2,2-dimethyl-2H-1-benzopyran from vanillin, epoxidation, then ring opening of the epoxide with nitrogen nucleophiles to produce the new benzopyrans. Biological testing showed a dramatic decrease in activity thus revealing an important site of activity in this class of compounds.

Animals↗
PubMed2001

Isolation, structure determination, and synthesis of neodysiherbaine A, a new excitatory amino acid from a marine sponge.

[structure: see text] A new excitatory amino acid, neodysiherbaine A (2), was isolated as a minor constituent of the aqueous extract from the marine sponge Dysidea herbacea. The structure was deduced by spectroscopic methods and established unambiguously by the total synthesis. The present synthesis, including as a key step cross-coupling of the 6/5-bicyclic core with an amino acid residue, is useful in constructing its structural analogues.

Alanine↗
PubMed2000

Mechanistic aspects of the metabolism of 1,3-dichloropropene in rats and mice.

1,3-Dichloropropene (DCP) is used in agriculture for the control of nematodes in a variety of food crops. The major routes of metabolism for this halogenated aliphatic compound involve conjugation with glutathione and oxidation to carbon dioxide. An additional, minor route of metabolism proposed for this compound involves epoxidation to the corresponding 1,3-dichloropropene oxide (DCPO). Recent in vivo studies have provided evidence for the formation of DCPO in mice following intraperitoneal (ip) administration of 350-700 mg of DCP/kg, which is equal to, or exceeds, the reported oral LD(50) for this compound in mice [Schneider, M., et al. (1998) Chem. Res. Toxicol. 11, 1137-1144]. The potential for epoxidation of DCP in rats and mice at lower doses administered orally was therefore examined. Following oral administration of 100 mg of DCP/kg of body weight to F344 rats and B(6)C(3)F(1) mice, no DCPO was found in the liver or blood 0-90 min postdosing at a relatively low detection limit (10 ng/g of tissue). Only very low levels of DCPO were seen following ip administration of 100 mg of DCP/kg of body weight in blood of B(6)C(3)F(1) mice. Substantial levels of DCPO were only seen as a metabolite of DCP following ip administration of 700 mg of DCP/kg to B(6)C(3)F(1) or Swiss-Webster mice. Significant nonlinearity of DCP epoxidation was evident following ip administration, with approximately 130-fold less DCPO in mice given 100 vs 700 mg/kg. The time course of DCPO formation could only be followed for 76 min, due to 100% mortality in Swiss-Webster mice at the 700 mg/kg dose level. The formation of measurable DCPO in mice was also accompanied by acute hepatic damage following ip administration of 100 or 700 mg of DCP/kg to mice. In contrast, no evidence of acute toxicity was noted in mice treated with 100 mg/kg via oral gavage. These data suggest that measurable epoxidation of DCP to DCPO, in the rodent, occurs only at relatively high dose levels which result in acute hepatic injury or death. It was concluded that findings of DCPO formation at lethal doses administered via bolus internal injections do not reflect DCPO formation at lower doses administered via the natural portal of entry.

Administration, Oral↗
PubMed2003

Calcium salts in the treatment of hyperphosphatemia in hemodialysis patients.

PURPOSE OF REVIEW: Hyperphosphatemia in patients with end-stage renal disease leads to secondary hyperparathyroidism and renal osteodystrophy, and is independently associated with mortality risk. How hyperphosphatemia increases mortality risk is unknown but it may promote cardiovascular calcification. It is recommended that dialysis patients be treated to maintain normal serum phosphorus. Although calcium-based phosphate binders are cost-effective, their long-term safety has been questioned because of their postulated role in progression of cardiovascular calcification. In this regard, sevelamer hydrochloride has been recommended as an alternative phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders. RECENT FINDINGS: Results from the calcium acetate Renagel evaluation study indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorus and calcium x phosphorus product in hemodialysis patients. However, in the Treat-to-Goal study dialysis patients treated with sevelamer had less progression of coronary and aortic calcification than patients treated with calcium-containing binders. The mechanism underlying the slower rate of progression of cardiovascular calcification in sevelamer-treated patients remains uncertain but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol. SUMMARY: At present, evidence incriminating calcium-containing phosphate binders in the progression of cardiovascular calcification in end-stage renal disease remains largely circumstantial. As calcium acetate is more efficacious and cost-effective than sevelamer, it remains an accepted first-line drug. Treatment with sevelamer hydrochloride should be considered for patients with persistent hypercalcemia during calcium-based binder therapy despite appropriate adjustment of vitamin D therapy.

Acetates↗
PubMedDate not supplied

Examination of low-incidence brain tumor responses in F344 rats following chemical exposures in National Toxicology Program carcinogenicity studies.

Neoplasms in the brain are uncommon in control Fischer 344 (F344) rats; they occur at a rate of less than 1% in 2-yr toxicity/carcinogenicity studies. Furthermore, only 10 of nearly 500 studies conducted by the National Toxicology Program (NTP) showed any evidence of chemically related neoplastic effects in the brain. Generally, the brain tumor responses were considered equivocal, because the characteristics of potential neurocarcinogenic agents (such as statistically significant increased incidences, decreased latency and/or survival, and demonstration of dose-response relationships) were not observed. A thorough examination, including comparisons with a well-established historical database, is often critical in evaluating rare brain tumors. Chemicals that gave equivocal evidence of brain tumor responses were generally associated with carcinogenicity at other sites, and many chemicals were mutagenic when incubated with metabolic activating enzymes. Other factors that were supportive of the theory that marginal increases in brain tumor incidence were related to chemical exposure were that (a) some of the tumors were malignant, (b) no brain neoplasms were observed in concurrent controls from some studies, and/or (c) brain tumors were also seen following exposure to structurally related chemicals. In 2-yr studies in F344 rats (studies conducted by the NTP), equivocal evidence of carcinogenicity was observed for the following 9 chemicals: isoprene, bromoethane, chloroethane, 3,3'-dimethylbenzidine dihydrochloride, 3,3'-dimethoxybenzidine dihydrochloride, furosemide, C.I. direct blue 15, diphenhydramine hydrochloride, and 1-H-benzotriazole. Glycidol was the only chemical evaluated by the NTP with which there was clear evidence of brain tumor induction in F344 rats. Clarification of the potential neurocarcinogenic risks of chemicals that produce equivocal evidence of a brain tumor response in conventional 2-yr rodent studies may be aided by the use of transgenic mouse models that exhibit genetic alterations that reflect those present in human brain tumors as well as by the use of in utero exposures.

Animals↗
PubMed2001

Metabolism of butadiene monoxide by freshly isolated hepatocytes from mice and rats: different partitioning between oxidative, hydrolytic, and conjugation pathways.

1,3-Butadiene (BD) is a multisite carcinogen in rodents, with mice being much more susceptible than rats. This species difference in carcinogenicity has been attributed to differences in metabolism. In this study, coordinated metabolism of butadiene monoxide (BMO, 5, 25, and 250 microM), the primary reactive metabolite of BD, was investigated in freshly isolated male B6C3F1 mouse and Sprague-Dawley rat hepatocytes. The hepatocytes from both species catalyzed BMO oxidation to meso- and (+/-)-diepoxybutane (DEB), BMO hydrolysis to 3-butene-1,2-diol (BDD), and BMO conjugation with glutathione (GSH) to form GSH conjugates (GSBMO). Metabolite area under the curve (AUC) exhibited dependence on the BMO concentration and incubation time (0-45 min). However, the observed BMO activation/detoxication ratios (obtained by dividing the AUC for total DEB by the summed AUC values for BDD and GSBMO) with mouse hepatocytes were approximately 15- to 40-fold higher than the corresponding ratios observed with rat hepatocytes. At 5 microM BMO, bioactivation in the mouse exceeded detoxication by approximately 2-fold, whereas at the 250 microM concentration, activation was only about 31% of total detoxication. In rat hepatocytes, the activation-detoxication ratio was relatively independent of the initial BMO concentration, with flux through the oxidative pathway at approximately 2 to 5% of the total detoxication. These results, which are more consistent with in vivo mouse and rat toxicity data than the metabolic rates obtained with subcellular fractions, illustrate the potential utility of the isolated hepatocyte model for estimating flux through competing metabolic pathways and predicting in vivo metabolism of BMO and its parent compound, BD.

Animals↗
PubMedDate not supplied

An oxidized derivative of linoleic acid affects aldosterone secretion by adrenal cells in vitro.

Based on the clinical observation that humans with visceral adiposity have higher plasma aldosterone levels than controls, we postulated that endogenous fatty acids can be oxidized by the liver to form stimuli of the adrenal cortex. Although we could show that hepatocytes produced adrenal stimuli from linoleic acid in vitro, the yield was very small. To facilitate the elucidation of chemical structures, we incubated a large amount of linoleic acid with lipoxygenase, then treated the hydroperoxide with cysteine and iron. The major product of this process was 12,13-epoxy-9-keto-10-trans-octadecenoic acid. This epoxy-keto compound stimulated aldosterone production at concentrations from 0.5 to 15 microm. At higher concentrations, it was inhibitory. The epoxy-keto-octadecenoic acid exhibited the chromatographic characteristics of one product of the incubation of linoleic acid with hepatocytes. The results are consistent with the postulated conversion of linoleic acid to stimuli of aldosterone production. This may be a mechanistic link between visceral obesity and hypertension in humans.

Aldosterone↗
PubMedDate not supplied

The cytotoxic and mutagenic properties of cholesterol oxidation products.

The oxidation of cholesterol proceeds as part of the lipid peroxidation process in membranes. Several oxidation products characteristic of a free-radical mechanism are formed and some can serve as indices of the nature and extent of cholesterol oxidation and of lipid peroxidation in general. Among the most typical oxidation products of lipid peroxide-dependent propagation reactions are the enantiomeric 5,6-epoxides and 7-ketocholestanol. Small amounts of these compounds may persist in tissues experiencing lipid peroxidation at a low but steady flux of free-radical reactions. Supporting evidence includes the routine detection of small quantities of cholesterol epoxides in tissues of normal animals, and the increase of these epoxides under conditions of oxidant stress or antioxidant deficiency. Conversion of cholesterol epoxides to cholestane triol is expected in cells possessing cholesterol epoxide hydrolase. All of these oxidation products possess remarkable cytotoxicity (at least part of which may be due to effects on the cell membrane) causing an increase in intracellular calcium. The cholesterol epoxides are also weakly mutagenic, although the mechanism for this mutagenicity remains to be clarified. In contrast, the other lipid epoxides normally encountered in tissues (chiefly fatty acid epoxides) are not mutagenic, and are much less toxic than the oxysterols described. The cytotoxicity of several oxysterols may be due to a number of mechanisms. That only the epoxides are mutagenic suggests that genotoxicity is a function of their electrophilic reactivity. This is not consistently apparent with the other compounds examined.

Animals↗
PubMed2005

A computational study of carbocations from oxidized metabolites of dibenzo[a,h]acridine and their fluorinated and methylated derivatives.

In a model computational study aimed at understanding structure-reactivity relationships and substituent effects on carbocation stability in aza-polycyclic aromatic hydrocarbons, the epoxides, diol epoxides, and the dihydrodiols of dibenzo[a,h]acridine (DB[a,h]ACR) were studied by density functional theory at the B3LYP/6-31G level. Bay region carbocations were formed via the O-protonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (polarized continuum model method). Charge delocalization modes in the resulting carbocations were deduced by gauge-independent atomic orbitals (GIAO) NMR (based on Delta delta13C values) and via the natural population analysis (NPA)-derived changes in charges. Although the solvent decreases the exothermicity of the epoxide ring-opening reactions due to greater stabilization of the reactants, relative reactivity trends remain the same. Whereas fluorine substitution at ring positions bearing significant positive charge leads to carbocation stabilization by fluorine p-pi back-bonding, fluorine substitution at a ring position that presented negative charge density in the unsubstituted compound leads to inductive destabilization. Methylated derivatives exhibit less sensitivity to substituent effects as compared to the fluorinated analogues. A bay region methyl group produces structural distortion, and this deviation from planarity destabilizes the epoxide, favoring ring opening. Relative energies, changes in NPA charges, and GIAO NMR data in the resulting "benzylic" carbocations are examined collectively and discussed, taking into account the available biological activity data on these compounds.

Acridines↗
PubMed1994

Modification of myosin isozymes and SR Ca(2+)-pump ATPase of the diabetic rat heart by lipid-lowering interventions.

To define metabolic influences on cardiac myosin expression and sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase streptozotocin-diabetic rats were treated for 9-10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I (CPT-1) and fatty acid synthesis, or an antilipolytic drug, acipimox. Etomoxir reduced myosin V3 of diabetic rats but did not normalize it. However, the high serum triglyceride, free-fatty acid and cholesterol concentrations in diabetic animals were greatly reduced. After bypassing the CPT-1 inhibition with a medium-chain fatty acid (miglyol) diet, the V3 contents and serum lipids were still reduced in the etomoxir-treated diabetic rats; V3 was also reduced in diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or triiodothyronine concentrations in diabetic rats were not improved by these interventions but changes in V3 were correlated with those in triglyceride, free-fatty acid and cholesterol concentrations, it is likely that myosin may be influenced by some metabolic factors. To assess the role of adrenergic influences, diabetic rats (7-8 wk) were treated with an antisympathotonic drug, moxonidine, a beta-adrenoceptor blocking drug, propranolol, and a bradycardic drug, tedisamil. Myosin V3 was not reduced significantly in moxonidine-treated or propranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid hormones and insulin were not altered, whereas triglycerides were reduced but not significantly by these antiadrenergic agents. Lowering serum lipids in diabetic rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR Ca(2+)-stimulated ATPase activity. On the other hand, in diabetic rats treated with moxonidine, propranolol or tedisamil, the ATPase activity was not increased significantly. These results suggest that normalization of blood lipids is important for improving subcellular organelle function in diabetic hearts with impaired glucose utilization.

Animals↗
PubMed2001

Aromatic dental monomers affect the activity of cholesterol esterase.

The dental restorative monomer, BISGMA (2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane), and bisphenol A diglycidyl ether (BADGE) increase the velocity of the reaction catalyzed by pancreatic cholesterol esterase (CEase, bovine). The metabolite of these monomers, bisphenol A bis(2,3-dihydroxypropyl) ether, and a common plasticizer, di-2-ethylhexyl phthalate (DEHP), also increase the velocity of CEase-catalyzed ester hydrolysis. BISGMA at concentrations of 1.5-8.0 microM increases the velocity to 126-169% of its value in the absence of BISGMA. Increasing BISGMA above 8 microM caused no further increase in velocity. BADGE at 7-25 microM increases the velocity to 112-205% of its value without BADGE. The metabolite of BISGMA and BADGE at concentrations of 2.0-7.1 microM increases the velocity to 103-113% of its value without metabolite. DEHP at concentrations of 0.52-4.3 microM increases the velocity to 108-187% of its value without DEHP. On the other hand, bisphenol A dimethacrylate is a competitive inhibitor of CEase, with a K(i) of 3.1 microM.

Benzhydryl Compounds↗
PubMed2005

Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis.

Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis. Hyperphosphatemia in patients with ESRD leads to secondary hyperparathyroidism, renal osteodystrophy, and is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. National Kidney Foundation K/DOQI bone metabolism and disease guidelines recommend maintenance of serum phosphorus (P) below 5.5 mg/dL, and Ca x P product less than 55 mg(2)/dL(2). Although calcium-based phosphate binders (CBPB) are cost effective, long-term safety concerns relate to their postulated role in progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE study) indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorous and Ca x P product in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer is unknown, but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol in sevelamer-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in ESRD remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer, it remains an accepted first-line phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders in patients on maintenance hemodialysis.

Acetates↗
PubMed1984

Subcellular distribution of styrene oxide in rat liver.

The subcellular distribution of (3H )-styrene-7,8-oxide was studied in the rat liver. The compound was added to liver homogenate to give a final concentration of 2 X 10(-5); 2 X 10(-4) and 2 X 10(-3) M. Subcellular fractions were obtained by differential centrifugation. Most of styrene oxide (59-88%) was associated with the cytosolic fraction. Less than 15 percent of the compound was retrieved in each of the nuclear, mitochondrial and microsomal fractions. A considerable percentage of radioactivity was found unextractable with the organic solvents, suggesting that styrene oxide reacted with the endogenous compounds. The intracellular distribution of this epoxide was also studied in the perfused rat liver. Comparable results with those previously described were obtained. The binding of styrene oxide to the cytosolic protein was investigated by equilibrium dialysis and ultrafiltration. Only a small percentage of the compound was bound to protein.

Animals↗