Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Epoxy Compounds”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 937 records · Page 52Linked to original sources
PubMed1996

Adducts to N-terminal valines in hemoglobin from butadiene metabolites.

In order to identify a hemoglobin adduct useful for monitoring of doses of butadiene metabolites, particularly the strongly genotoxic, bifunctional diepoxybutane (DEB), the reaction of DEB with valinamide, a relevant model of globin N-termini, was studied. A preliminary kinetic analysis showed that the primary reaction product of DEB with valine-N gives, as was expected, rise to a ring-closed pyrrolidine-structured compound, N,N-(2,3-dihydroxybuta-1,4-diyl)valine (PYRV), in a reaction which is fast when compared to hydrolysis of the second oxirane ring with formation of N-(2,3,4-trihydroxybutyl)valine (THBV). The ring closure is also fast when compared to the rate of formation of a cross-linked divaline product. PYRV can therefore be used as a specific marker of in vivo doses of DEB whereas THBV may be applied for the dosimetry of the metabolite (1,2-dihydroxyethyl)oxirane. The latter is formed by half-hydrolysis of DEB or oxygenation of 1,2-dihydroxy-3-butene. The N-alkyl Edman method, used for specific cleavage and gas chromatographic/mass spectrometric (GC/MS) determination of adducts to N-terminal valine in hemoglobin, could be used for measurement of THBV, as shown in alkylation experiments with blood. However, the adduct specific for DEB, PYRV, requires-due to its tertiary amine structure-other techniques. The reaction products were identified by GC/MS, PYRV by 13C and 1H NMR, and THBV because of its formation by reduction of the Schiff bases of threose and erythrose with hemoglobin.

Alkylation↗
PubMed2006

Cyclic AMP-dependent modulation of cardiac L-type Ca2+ and transient outward K+ channel activities by epoxyeicosatrienoic acids.

The three major enzyme systems, cyclo-oxygenase, lipoxygenase, and cytochrome P450 (P450/CYP), metabolize arachidonic acid (AA) to biologically active compounds. P450 and its associated monooxygenase activities have been identified in mammalian cardiac tissue, including humans. The four regioisomeric eicosanoids, 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) of AA metabolites derived by P450 epoxygenases have shown to possess potent biological effects in numerous tissues. In the coronary circulation the EETs are leading candidates for endothelial-derived hyperpolarizing factors that hyperpolarize vascular smooth muscle cells by opening Ca2+-activated K+ channels. Recently, the effects of the CYP pathways and their metabolites on cardiac ischemia-reperfusion injury have been evaluated in animal models. Some of these AA metabolites are cardioprotective and some are detrimental. However, EETs appear to be cardioprotective in CYP2J2 transgenic mice and in a canine ischemic model. Multiple effects of EETs on cardiac ion channels have been observed, such as activation of ATP-sensitive K+ channels and L-type Ca2+ channels in cardiomyocytes and inhibition of cardiac Na+ channels and L-type Ca2+ channels reconstructed in planar lipid bilayers. This brief review summarizes EET-induced modulation of cardiac ion channels.

8,11,14-Eicosatrienoic Acid↗
PubMed1993

Intestinal bacteria and endogenous production of malonaldehyde and alkylators in mice.

Association of intestinal bacteria with endogenous production of some reactive compounds was studied by determination of adducts to haemoglobin in blood from germ-free and corresponding control mice. N-terminal valines in haemoglobin were analysed with regard to adducts from malonaldehyde (MA), ethene/ethylene oxide, propene/propylene oxide and methylating agents. It was found that the adduct levels from MA were 1.65 and 3.32 nmol/g globin in germ-free and control mice, respectively. The levels of adducts from ethylene oxide and propylene oxide were 10.8 and 10.3 pmol/g globin, respectively, in germ-free and 21.7 and 17.7 pmol/g globin, respectively, in control mice. The level of adducts from endogenous methylating agents was higher in germ-free mice than in controls (473 and 408 pmol/g globin, respectively). These differences in adduct levels between germ-free and conventional mice are statistically significant. The causes of the observed variations are so far not identified. This study confirms earlier findings on background levels of adducts in unexposed individuals and supports the hypothesis that these adducts reflect the occurrence of reactive intermediates in vivo that may constitute cancer risks in background cancer incidence. The present study also shows that intestinal bacteria may be an important determinant of such endogenous risk factors.

Alkylating Agents↗
PubMed1982

Metabolism of benzo [a] pyrene by guinea pig adrenal and hepatic microsomes.

Studies were carried out to compare the metabolism of benzo [a] pyrene (BP) by adrenal and hepatic microsomes obtained from adult male guinea pigs. Adrenal microsomes produced fluorescent metabolites (primarily phenols) approximately three to four times more rapidly than hepatic microsomes, but the differences in the rates were considerably smaller when total BP metabolism was assessed using an isotopic assay. The apparent discrepancy between the two assays is attributable to differences in the profiles of BP metabolites produced by adrenal and liver. Separation of metabolites by high pressure liquid chromatography revealed that adrenal microsomes converted BP to primarily a phenolic metabolite with a retention time identical to that of 3-hydroxy-BP. Liver microsomes, by contrast, produced approximately equal amounts of compounds co-chromatographing with 3-hydroxy-BP and BP-4,5-dihydrodiol. Small amounts of other metabolites were also produced by adrenal and hepatic microsomes. Liver microsomes catalyzed the conversion of BP to metabolites that became covalently bound to exogenous DNA. The amount of binding was dependent upon the duration of incubation and concentration of microsomal protein. Adrenal microsomes, by contrast, did not promote BP binding to DNA. Inhibition of microsomal epoxide hydratase activity with trichloropropene oxide (TCPO) blocked the formation of dihydrodiol metabolites of BP by adrenal and liver microsomes. In the presence of TCPO, liver microsomes produced large amounts of a BP metabolite co-chromatographing with BP-4,5-oxide. TCPO also increased the rate of production of DNA-binding metabolites by liver microsomes but had no effect on the formation of DNA-binding metabolites by adrenal microsomes. The results demonstrate major differences in the pathways of BP metabolism by guinea pig adrenal and hepatic microsomes. Although adrenal microsomes metabolize BP more rapidly than hepatic microsomes, far greater amounts of reactive metabolites are produced by the liver. Thus, adrenal metabolism of BP may be of little toxicological significance.

Adrenal Glands↗
PubMed1990

Molecular dosimetry of polycyclic aromatic hydrocarbon epoxides and diol epoxides via hemoglobin adducts.

Ten reactive metabolites of five polycyclic aromatic hydrocarbons and styrene were investigated to determine the generality of ester adduct formation with human hemoglobin in the form of RBC and hydrolysis to the corresponding tetrahydrotetrols or dihydrodiols. No exceptions were noted among the compounds tested, which included the anti-diol epoxides of benzo[a]pyrene (BaP), chrysene, and benz[a]anthracene; the syn-diol epoxide of BaP; a mixture of syn- and anti-diol epoxides of benzo[e]pyrene; and epoxides of styrene, benzo[e]pyrene, BaP, and cyclopenta[c,d]pyrene. A test of the propensity of the simplest benzylic epoxide, styrene oxide, to form esters that hydrolyze via a BAL1 mechanism was performed. Hydrolysis of styrene oxide-adducted hemoglobin in H2(18)O at neutral pH yielded 18O incorporation results that suggest this mechanism of hydrolysis is operant to a minor degree in styrene oxide-hemoglobin ester adducts. A method was developed for the isolation and quantification of the polycyclic aromatic alcohols, which consists of enzymatic proteolysis, immunoaffinity chromatography, and gas chromatography-mass spectrometry or fluorimetry. The method allows for routine analysis of hemoglobin from individual samples as small as 1 ml of whole blood. Analysis of blood from different human populations revealed that hemoglobin adducts of the anti-diol epoxide of BaP dominated the spectrum of adducts formed by the selected metabolites.

Chromatography, Affinity↗
PubMed2006

Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation.

There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.

Animals↗
PubMed1993

Kinetic study of collagen fixation with polyepoxy fixatives.

A new biomaterial has been developed by fixing native collagen with a polyepoxy compound (PC) fixative. In this study, bovine internal thoracic arteries were fixed with PC under various conditions to help understand the kinetics of the collagen-PC reactions and optimize the fixation process. At predetermined time intervals, small samples were cut from the arteries to determine the quantities of the remaining unreacted amino acids in the collagen. Temperature, concentration, and solution pH were among the key parameters studied. The overall fixation rate was found to be reaction-rate controlled, as the rate of fixation was relatively slow compared with the rate of diffusion of PC. As might be expected, the reaction rate was favored by a higher temperature, concentration, and solution pH. A kinetic model, with a 2.5th reaction order with respect to the reactive functional groups of collagen and a first order with respect to PC, was developed that gave a good fit to the experimental data. Based on this model, the degree of fixation, X, as a function of time, t, is given by (1 - X)-1.5 = 1 + Kt, where K is a constant related to the initial concentrations and the reaction rate constant.

Amino Acids↗
PubMed1999

Simultaneous analysis of hemoglobin adducts of acrylamide and glycidamide by gas chromatography-mass spectrometry.

Acrylamide (AA) is a carcinogen in experimental animals. Glycidamide (GA), formed by metabolic epoxidation of AA, is believed to be responsible for the carcinogenicity of AA. Occupational exposure to AA has been assessed earlier by measurement of its adducts with N-terminal valine in hemoglobin. A background of AA adducts [N-(2-carbamoylethyl)valine (AAVal), about 30 pmol/g globin] was found in individuals without known exposure to the compound. The method previously available for adducts of GA only allowed analysis of samples from highly exposed individuals and showed similar levels of AAVal and adducts of GA [N-(2-hydroxy-2-carbamoylethyl)valine (GAVal)]. We have developed a sensitive method for simultaneous quantification of adducts of GA and AA, which is suitable down to low exposure levels. The method is based on the so-called modified Edman method, where globin is reacted with pentafluorophenyl isothiocyanate under neutral conditions. The valine adducts are then extracted in the form of pentafluorophenylthiohydantoin (PFPTH) derivatives. The analytical procedure included reaction of the PFPTH derivatives with acetic anhydride in order to protect the hydroxyl group of GAVal. The PFPTH derivatives of AAVal and GAVal were analyzed by gas chromatography/tandem mass spectrometry. ((2)H(3))AAVal-PFPTH was used as the internal standard. The method was applied to samples from 11 workers at an AA production plant, 1 nonexposed nonsmoker, and a few participants of a smoking cessation program. AAVal levels were in the range 27-1854 pmol/g globin. Recorded levels of GAVal were 3-12% of those of AAVal, suggesting that previous measurements of GAVal overestimate GAVal at low levels of exposure to AA.

Acrylamide↗
PubMed2003

Metabolic activation of a pyrazinone-containing thrombin inhibitor. Evidence for novel biotransformation involving pyrazinone ring oxidation, rearrangement, and covalent binding to proteins.

Compound I, (2-[3-[(2,2-difluoro-2(2-pyridyl)ethyl)amino]-6-methyl-2-oxohydropyrazinyl]-N-[(3-fluoro(2-pyridyl))methyl]acetamide, is a potent competitive inhibitor of thrombin that reacts stoichiometrically with the protease. Compounds of this class possess therapeutic potential as anticoagulation agents. During the metabolic characterization of compound I, evidence was obtained for extensive metabolic activation of the pyrazinone ring system. Following administration of (14)C-labeled I to rats, significant levels of irreversibly bound radioactivity to proteins were detected in rat plasma and liver. LC/MS/MS analysis of metabolites formed in rat and human liver microsomes fortified with glutathione (GSH) revealed the presence of two structurally distinct GSH adducts. It is proposed that the first of these GSH conjugates derives from a two electron oxidation of the 6-methyl-2-oxo-3-aminopyrazinone moiety to afford an electrophilic imine-methide intermediate, while the second is formed by addition of GSH to an epoxide formed by P-450-mediated oxidation of the double bond at the 5-6 position of the pyrazinone ring. The addition of GSH to the proposed epoxide facilitates opening of the pyrazinone ring and a rearrangement to afford a stable, rearranged imidazole-containing metabolite. Elucidation of the metabolic activation pathways of I provides structural guidance for the design of thrombin inhibitors with decreased potential for the generation of chemically reactive intermediates.

Administration, Oral↗
PubMed1986

Stereoselectivity of rat liver cytochrome P-450 isozymes: direct determination of enantiomeric composition of K-region epoxides formed in the metabolism of benz[a]anthracene and 7,12-dimethylbenz[a]anthracene.

The K-region 5,6-epoxides of benz[a]anthracene (BA) and 7,12-dimethylbenz[a]anthracene (DMBA) were isolated by normal-phase HPLC from metabolites formed by incubation of the respective parent compound with liver microsomes from untreated (control), phenobarbital (PB)-treated, and 3-methylcholanthrene (MC)-treated rats in the presence of an epoxide hydrolase inhibitor, 3,3,3-trichloropropylene 1,2-oxide. The enantiomeric contents of the metabolically formed K-region 5,6-epoxides of BA and DMBA were directly determined by chiral stationary phase HPLC. The K-region 5,6-epoxides formed in the metabolism of BA have (5R,6S): (5S,6R) enantiomer ratios of 25:75 (control), 21:79 (PB), and 4:96 (MC), respectively. In contrast, the (5R,6S):(5S,6R) enantiomeric ratios of the K-region 5,6-epoxides formed in the metabolism of DMBA are 76:24 (control), 80:20 (PB), and 97:3 (MC), respectively. These and earlier results on the stereoselective K-region metabolism studies of 7-methylbenz[a]anthracene and 12-methylbenz[a]anthracene indicate that cytochrome P-450 isozymes exhibit different stereoselectivities in the K-region epoxidations of BA and DMBA and a methyl substituent at the C12 position of BA alters the stereoheterotopic interactions between cytochrome P-450 isozymes and the BA molecule.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Gas chromatography-mass spectrometry of cis-9,10-epoxyoctadecanoic acid (cis-EODA). I. Direct evidence for cis-EODA formation from oleic acid oxidation by liver microsomes and isolated hepatocytes.

Oleic acid, cis-9-octadecenoic acid, is the major fatty acid in mammals. Its oxide, cis-9,10-epoxyoctadecanoic acid (cis-EODA), has been identified in blood and urine of humans, its origin is, however, still unknown. Lipid peroxidation and enzyme-catalyzed epoxidation of oleic acid are two possible sources. In the present article, we investigated by HPLC and GC-MS whether cis-EODA is formed enzymatically from oleic acid by the cytochrome P450 (CYP) system. Oleic acid, cis-EODA and its hydratation product threo-9,10-dihydroxyoctadecanoic acid (threo-DiHODA) were quantitated by HPLC as their p-bromophenacyl esters. For structure elucidation by GC-MS, the pentafluorobenzyl (PFB) esters of these compounds were isolated by HPLC and converted to their trimethylsilyl ether derivatives. Liver microsomes of rats, rabbits and humans oxidized oleic acid into cis-EODA. This is the first direct evidence for the enzymatic formation of cis-EODA from oleic acid. The epoxidation of oleic acid was found to depend on CYP, NADPH+H(+), and O(2). cis-EODA was measurable in incubates of liver microsomes for up to 30 min of incubation. Maximum cis-EODA concentrations were reached after 5-7 min of incubation and found to depend upon oleic acid concentration. Isolated rat hepatocytes hydratated cis-EODA into threo-DiHODA which was further converted to unknown metabolites. However, from incubation of oleic acid with these cells we could not detect threo-DiHODA or cis-EODA. Our study suggests that circulating and excretory cis-EODA may originate, at least in part, from CYP-catalyzed epoxidation of oleic acid. GC-MS of intact cis-EODA as its PFB ester in the negative-ion chemical ionization mode should be useful in investigating the physiological role of cis-EODA in man.

Animals↗
PubMed2005

Effects of efficient phosphate binding on bone in chronic renal failure rats.

BACKGROUND: We recently reported that administration of high doses of lanthanum carbonate (1000 mg/kg/day) to chronic renal failure (CRF) rats can result in a mineralization defect. Our results suggested, however, that the impaired mineralization was not due to a direct toxic action of lanthanum on the bone, but rather was an indirect consequence of a phosphate depletion resulting from the compound's high phosphate-binding capacity. To further substantiate these results, in the present study, the effects of lanthanum carbonate on bone were compared to the effects of sevelamer, a nonabsorbed, non-metal-containing polymeric phosphate-binding agent. METHODS: Male Wistar rats underwent a 5/6th nephrectomy to induce chronic renal failure, after which they were treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) by oral gavage for 12 weeks. RESULTS: CRF animals treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) developed a phosphate depletion after 4 weeks of treatment, as evidenced by a marked reduction in phosphaturia. At sacrifice after 12 weeks of treatment, bone histomorphometry showed that a mineralization defect had developed in two out of six animals in the lanthanum-carbonate-treated group, in four out of seven animals in the 1000 mg/kg/ day sevelamer group, and in one out of nine animals in the 500 mg/kg/day sevelamer group. CONCLUSIONS: These results corroborate our previous findings that the administration of a powerful phosphate-binding agent to CRF rats can induce phosphate depletion, resulting in a mineralization defect.

Animals↗
PubMed2000

Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines.

Recently, three natural products have been identified, the epothilones, eleutherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitotic phase of the cell cycle. In this report, we have compared and contrasted the effects of these new agents in Taxol-sensitive and -resistant cell lines. We also have taken advantage of a human lung carcinoma cell line, A549-T12, that was isolated as a Taxol-resistant cell line and found to require low concentrations of Taxol (2-6 nM) for normal cell division. This study then examined the ability of these new compounds to substitute for Taxol in sustaining the growth of A549-T12 cells. Immunofluorescence and flow cytometry have both indicated that the epothilones and eleutherobin, but not discodermolide, can substitute for Taxol in this Taxol-dependent cell line. In A549-T12 cells, the presence of Taxol significantly amplified the cytotoxicity of discodermolide, and this phenomenon was not observed in combinations of Taxol with either the epothilones or eleutherobin. Median effect analysis using the combination index method revealed a schedule-independent synergistic interaction between Taxol and discodermolide in four human carcinoma cell lines, an effect that was not observed between Taxol and epothilone B. Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increase in the hypodiploid population, thereby indicating that a possible mechanism for the observed synergy is the potentiation of apoptosis. Our results suggest that Taxol and discodermolide may constitute a promising chemotherapeutic combination.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Isolation from pig liver microsomes, identification by tandem mass spectrometry and in vitro immunosuppressive activity of an SDZ-RAD 17,18,19,20,21,22-tris-epoxide.

Macrolide immunosuppressive drugs such as tacrolimus (FK506) and sirolimus (rapamycin) are compounds largely used in modern immunosuppressive therapy and considered as powerful immunosuppressive agents. Some of these molecules are still under clinical development as, for example, SDZ-RAD (40-O-(2-hydroxyethyl)rapamycin), an immunosuppressive drug closely related to rapamycin. SDZ-RAD has a molecular mass of 957.57 Da (C53H83NO14) and shares the same common intracellular receptor as tacrolimus, the FK-506 binding protein (FKBP-12). SDZ-RAD exerts its pharmacological effect by binding to a different effector protein, inhibits the S6p 70-kinase and interrupts a different signal transduction pathway than tacrolimus. Both SDZ-RAD and rapamycin are metabolized mainly by the cytochrome P-450 3A4-dependent mixed function oxygenase enzyme system to hydroxylated and demethylated metabolites. We describe here the isolation from pig liver microsomes of a novel SDZ-RAD metabolite identified by electrospray tandam mass spectrometry as a new SDZ-RAD 17,18,19,20,21,22-tris-epoxide metabolite. The in vitro immunosuppressive activity as measured by the mixed lymphocyte reaction is more or less comparable to that of SDZ-RAD, although its pharmacological mode of action may be different from that classically described for rapamycin.

Animals↗
PubMed2003

Hemoglobin adducts from glycidamide: acetonization of hydrophilic groups for reproducible gas chromatography/tandem mass spectrometric analysis.

Acrylamide (AA) is a reactive compound widely used as an industrial chemical. It is also, as recently shown, present in heated foodstuffs. AA is known to cause tumors in rodents and is classified as probably carcinogenic to humans. The metabolite glycidamide (GA) is assumed to be the predominant genotoxic agent in AA exposure. Therefore, knowledge about in vivo doses of GA is essential for cancer risk assessment of exposure to AA. The in vivo dose of GA could be inferred from the level of the adduct formed by GA with N-terminal valine (GA-Val) in hemoglobin (Hb), detached as a pentafluorophenylthiohydantoin (PFPTH) and measured by gas chromatography/tandem mass spectrometric (GC/MS/MS) analysis. However, due to the highly polar character of the GA-Val-PFPTH derivative, it was found necessary to modify the method through further derivatization. This paper presents an evaluation of acetonization for derivatization of the adjacent bond;OH and bond;NH(2) groups in the adduct formed from GA. Good reproducibility was obtained. Also, acetonization improves the response and thus increases the sensitivity of the GC/MS/MS analysis of the PFPTH derivative of GA-Val. The sensitivity obtained is sufficient for studies of background adduct levels of GA in animals and in humans. Acetonization as a method for derivatization is robust and simple.

Acetone↗
PubMed2000

Redox-dependent toxicity of diepoxybutane and mitomycin C in sea urchin embryogenesis.

The effects and mechanisms of action of diepoxybutane (DEB) and mitomycin C (MMC) were investigated on sea urchin embryogenesis, (Sphaerechinus granularis and Paracentrotus lividus). DEB- and MMC-induced toxicity was evaluated by means of selected end-points, including developmental defects, cytogenetic abnormalities and alterations in the redox status [oxygen-dependent toxicity, Mn-superoxide dismutase (MnSOD) and catalase activities and glutathione (GSH) levels]. Both DEB and MMC exhibited developmental toxicity (at concentrations ranging from 3 x 10(-5) to 3 x 10(-4) M and 3 x 10(-6) to 3 x 10(-5) M, respectively) expressed as larval abnormalities, developmental arrest and mortality. The developmental effects of both compounds were significantly affected by oxygen at levels ranging from 5 to 40%. These results confirmed previous evidence for oxygen-dependent MMC toxicity and are the first report of oxygen dependence for DEB toxicity. Both DEB and MMC exerted significant cytogenetic abnormalities, including mitotoxicity and mitotic aberrations, but with different trends between the two chemicals, at the same concentrations as exerted developmental toxicity. The formation of reactive oxygen species was evaluated using: (i) luminol-dependent chemiluminescence (LDCL); (ii) reactions of the main antioxidant systems, such as GSH content and MnSOD and catalase activities. The results point to clear-cut differences in the effects induced by DEB and MMC. Thus, DEB suppressed GSH content within the concentration range 10(-7)-3 x 10(-5) M. The activity of catalase was stimulated at lower DEB levels (10(-7)-10(-6) M) and then decreased at higher DEB concentrations (> or =10(-5) M). Increasing MMC concentrations induced LDCL and MnSOD activity (> or =10(-6) M) greatly and modulated catalase activity (10(-7) - 10(-6) M). GSH levels were unaffected by MMC. The results suggest that oxidative stress contributes to the developmental and genotoxic effects of both toxins studied, although through different mechanisms.

Animals↗
PubMed1979

Tumorigenicity of the diastereomeric benz[a]anthracene 3,4-diol-1,2-epoxides and the (+)- and (-)-enantiomers of benz[a]anthracene 3,4-dihydrodiol in newborn mice.

The tumorigenic activity of benz[a]anthracene (BA), the (+)- and (-)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BA 3,4-dihydrodiol), and the racemic diastereomers of the BA 3,4-diol-1,2-epoxides [i.e., either or both of the diastereomeric 1,2-epoxides derived from BA 3,4-dihydrodiol in which the epoxide oxygen is cis (diol epoxide-1) or trans (diol epoxide-2) to the benzylic 4-hydroxyl group) was examined in newborn Swiss-Webster mice. The mice were administered ip a total dose of 280 nmoles of compound in divided doses consisting of 40 nmoles within 24 hours of birth, 80 nmoles at 8 days of age, and 160 nmoles at 15 days of age. The experiment was terminated when the animals were 26 weeks of age. BA 3,4-diol-1,2-epoxide-2 was the most potent compound tested. All animals treated with BA 3,4-diol-1,2-epoxide-2 developed pulmonary tumors with an average of 13.3 tumors per mouse. BA 3,4-diol-1,2-epoxide-1 produced pulmonary tumors in 42% of the mice with an average of only 0.56 tumors per mouse. The (-)-enantiomer of BA 3,4-dihydrodiol with [3R,4R] absolute stereochemistry was the second most tumorigenic derivative of BA tested; it produced pulmonary tumors in 71% of the mice with an average of 1.88 tumors per mouse. BA and the (+)-enantiomer of BA 3,4-dihydrodiol had little or no tumorigenic activity at the dose tested. A comparison of the average number of pulmonary tumors per mouse revealed that BA 3,4-diol-1,2-epoxide-2 was about 30-fold more tumorigenic than was BA 3,4-diol-1,2-epoxide-1, 8-fold more tumorigenic than was (-)-BA 3,4-dihydrodiol, and greater than 85-fold more tumorigenic than was BA. These data indicate that in newborn mice BA 3,4-dihydrodiol and a BA 3,4-diol-1,2-epoxide are proximate and ultimate carcinogenic metabolites of BA, respectively.

Animals↗
PubMed1986

Rabbit pulmonary cytochrome P-450 monooxygenase system: isozyme differences in the rate and stereoselectivity of styrene oxidation.

The rate and stereoselectivity of the cytochrome P-450 (P-450)-dependent oxidation of styrene to styrene 7,8-oxide (SO) were determined in rabbit pulmonary microsomes and with purified rabbit pulmonary P-450 isozymes in reconstituted monooxygenase systems. Stereoselectivity was determined by separation of the diastereomeric SO-glutathione adducts by high-performance liquid chromatography; these four compounds accounted for more than 95% of the SO formed. Pulmonary microsomes preferentially formed (R)-SO [(R)-SO/(S)-SO = 1.6] at a rate of 7.5 nmol of SO formed/min/nmol of P-450. Antibodies to NADPH-P-450 reductase (antireductase) inhibited SO formation in pulmonary microsomes by greater than 98%. In the presence of antibodies to P-450 form 2 (anti-2), pulmonary microsomes oxidized styrene to equal amounts of (R)- and (S)-SO at a rate of 4.2 nmol of SO/min/nmol of total P-450; in the presence of antibodies to P-450 form 5 (anti-5), styrene was stereoselectively oxidized to (R)-SO [(R)-SO/(S)-SO = 2.0] at a rate of 6.5 nmol of SO/min/nmol of total P-450. In reconstituted monooxygenase systems, P-450 forms 2, 5 and 6 oxidized styrene to SO at rates of 10.0, 4.7 and 4.5 nmol of SO formed/min/nmol of P-450, respectively. The relative amounts of (R)-SO and (S)-SO produced were 2.0, 1.0 and 0.9, respectively. Predicted values for rate and stereoselectivity of styrene oxidation by pulmonary microsomes, calculated from the values obtained in the reconstitution experiments and the relative concentrations of the different P-450 isozymes, agreed well with experimentally determined values.

Animals↗