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Acrylamide is metabolized to glycidamide in the rat: evidence from hemoglobin adduct formation
No full textAcrylamide is an important industrial chemical which is neurotoxic to experimental animals as well as humans and recently has been shown to be mutagenic and carcinogenic. Despite much research it is still unclear whether the parent compound or a metabolite is responsible for the observed toxic effects. Contradictory results as to the role of cytochrome P-450 mediated metabolism of acrylamide in the induction of neurotoxic effects prompted us to investigate the possible formation of glycidamide, a reactive epoxide metabolite. The formation of this epoxide was strongly indicated by the identification by means of gas chromatography-mass spectrometry of derivatized S-(2-carboxy-2-hydroxyethyl)cysteine in hydrolyzed hemoglobin samples from rats treated with acrylamide in vivo and in microsomal suspensions of acrylamide with cysteine in vitro. This amino acid was found to be present in uninduced and phenobarbital-induced Sprague-Dawley rats and absent in controls, but occurred in lower amounts than the adduct derived from the parent compound, S-(2-carboxyethyl)cysteine. This finding suggests that the possible role of glycidamide in the neurotoxicity and carcinogenicity of acrylamide should be evaluated further
Evaluation of the neurotoxicity of glycidamide, an epoxide metabolite of acrylamide: behavioral, neurochemical and morphological studies
No full textAcrylamide is an important chemical used in the synthesis of polyacrylamides, which have a wide variety of industrial applications. The principal toxic effect of acrylamide, both in animals and in humans, is neurotoxicity. Peripheral nervous system effects are most prominent, but central nervous system effects have also been reported. Acrylamide is metabolized to the epoxide glycidamide, whose adducts to hemoglobin and to DNA have been identified in animals and humans. This metabolite may be involved in the reproductive and carcinogenic effects of acrylamide. In the present study we investigated whether glycidamide would exert neurotoxic effects similar to those caused by its parent compound. Male rats were injected i.p. with acrylamide (25 or 50 mg/kg) or glycidamide (50 or 100 mg/kg) daily for 8 days. Reduced weight gain was evident in animals exposed to glycidamide or to the higher dose of acrylamide. Both compounds induced lethargy and ataxia, but the posture of glycidamide-treated rats differed from that of animals treated with acrylamide. At the high doses, both compounds significantly affected rats' behavior in the rotarod test; on the other hand, only acrylamide was effective in the hindlimb splay test. Acrylamide inhibited activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in sciatic and tibial nerves, as well as in brain. Glycidamide inhibited GAPDH activity only in brain and activity of creatine kinase in both peripheral and central tissues. Acrylamide also caused profound urinary retention and distended bladders, while the effects of glycidamide were minimal. Morphological abnormalities were seen in sciatic nerves and dorsal root ganglion cells of rats treated with acrylamide (50 mg/kg x 12), but not in rats exposed to glycidamide (100 mg/kg x 11). These results indicate that the toxicities of acrylamide and glycidamide differ and suggest that acrylamide itself may be primarily responsible for its peripheral neurotoxicity
Formation of hemoglobin adducts of acrylamide and its epoxide metabolite glycidamide in the rat
No full textA method was developed for the determination of hemoglobin (Hb) adducts formed by the neurotoxic agent acrylamide and its mutagenic epoxide metabolite glycidamide. The method was based on simultaneous measurements of the cysteine adducts formed by these two agents by means of gas chromatography/mass spectrometry in hydrolyzed hemoglobin samples. Rats were injected ip with acrylamide or glycidamide in doses ranging from 0 to 100 mg/kg body wt, and the hemoglobin adduct levels were determined. The hemoglobin binding index of acrylamide to cysteine was found to be 6400 pmol (g Hb)-1/mumol (kg body wt)-1, higher than for any other substance studied so far in the rat, and 1820 pmol (g Hb)-1/mumol (kg body wt)-1 for glycidamide. In rats injected with acrylamide, formation of adducts of the parent compound was approximately linear with dose (0-100 mg/kg), whereas adducts of the epoxide metabolite glycidamide generated a concave curve, presumably reflecting the Michaelis-Menten kinetics of its formation. On the basis of the rate constants for cysteine adduct formation determined in vitro, the first-order rates of elimination of acrylamide and glycidamide from the blood compartment of rats were estimated to be 0.37 and 0.48 hr-1, respectively, using a linear kinetic model. It was further estimated that the percentage of acrylamide converted to glycidamide in the rat decreased from 51% following administration of 5 mg/kg to 13% after a dose of 100 mg/kg. Subchronic treatment of rats with acrylamide (10 mg/kg/day for 10 days or 3.3 mg/kg/day for 30 days) confirmed that the conversion rate of acrylamide to glycidamide, as determined from hemoglobin adduct formation, is higher at low-administered doses. These findings suggest that dose-rate effects may significantly affect risk estimates of this compound and that different low-dose extrapolation procedures should be employed for effects induced by the parent compound acrylamide and those induced by the metabolite glycidamide
Determination of hemoglobin adducts in humans occupationally exposed to acrylamide
No full textHemoglobin (Hb) adduct determinations were used to monitor occupational exposure to acrylamide (AA) and acrylonitrile (AN). Forty-one workers in a factory in the People's Republic of China who were involved in the synthesis of AA by catalytic hydration of AN and the manufacturing of polyacrylamides were studied. Ten nonexposed workers in the same city served as controls. AA and AN exposures were monitored using the modified Edman degradation procedure for the determination of their respective Hb adducts to N-terminal valine. The adduct levels in the exposed workers were 0.3-34 nmol/g Hb for AA and 0.02-66 nmol/g Hb for AN, as determined by gas chromatography-mass spectrometry (GC-MS). The formation of glycidamide (GA), the epoxide metabolite of AA, in humans was demonstrated by GC-MS analysis of its Hb adduct to N-terminal valine following acid hydrolysis, ion-exchange chromatography, and derivatization. The GA adduct was detected in samples from the exposed persons with levels of 1.6-32 nmol/g Hb. There was a linear relationship between the AA and GA adduct levels (r = 0.96) and the ratio of the in vivo doses of GA and AA was 3:10. These results suggest that AA is metabolized to GA in humans, as had previously been shown in the rat. The high AA adduct levels in the exposed workers, as compared to those expected from air concentrations, indicate that dermal exposure may contribute significantly to the total uptake of AA. The average daily in vivo doses of AA and GA in the highest exposed workers were comparable to the in vivo doses in rats injected with 3 mg/kg AA. Since a regimen of 2 mg/kg/day is known to cause a significant increase of tumors in rats, preventive measures may be necessary for humans exposed to high levels of AA in industrial settings
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Linear versus nonlinear models for hemoglobin adduct formation by acrylamide and its metabolite glycidamide: implications for risk estimation
No full textHemoglobin cysteine adduct levels formed by acrylamide (AA) and its epoxide metabolite glycidamide (GA) as previously determined (Bergmark et al., Toxicol. Appl. Pharmacol., 111: 352-363, 1991) in rats given single injections of AA were used to estimate tissue doses, D = integral of Cdt (area under the concentration curve in the blood compartment), of the two compounds. The data were adapted to linear or nonlinear kinetic models, where the latter model accounted for the Michaelis-Menten kinetics of the metabolic conversion of AA to GA. In the linear model, the first-order rates, k*, of elimination from all processes were estimated to be 0.50 and 0.48 h-1 for AA and GA, respectively. In the nonlinear model, the parametrical values Vmax = 19.1 h-1 and Km = 66 microM for the in vivo metabolic conversion of AA to GA, and k1 = 0.21 h-1 and k2 = 0.48 h-1 for the first-order rates of elimination from all other processes of AA and GA, respectively, were found to give the best fit to the exact dosimetric expressions [formula: see text] Using Equation B, it was estimated that the percentage of AA converted to GA approaches 58% when [AA]o, the initial concentration of AA, approaches zero. The implications for high-to-low-dose extrapolation of toxic effects of the derived mathematical relationships between administered dose and tissue dose are discussed
Comparative studies on the neuro- and reproductive toxicity of acrylamide and its epoxide metabolite glycidamide in the rat.
No full textThe results of this study suggest that acrylamide may be effective per se in causing peripheral nervous system damage in rats after repeated exposure to toxic doses (25-50 mg/gkg/day) whereas other toxic effects of this agent, such as reproductive toxicity appear to be mediated by the metabolite glycidamide
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