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PubMed1981

Effects of aspirin and acetaminophen in gastrointestinal hemorrhage. Results from the Boston Collaborative Drug Surveillance Program.

All patients observed in this analysis of the Boston Collaborative Drug Surveillance Program data had no known disease predisposing them to gastrointestinal (GI) bleeding. Major GI bleeding occurred in hospitalized patients recently exposed to ethacrynic acid (5/111; 4.5%), heparin sodium (7/575; 1.2%), corticosteroids (7/1,484; 0.5%), aspirin (6/2,081; 0.3%), and warfarin sodium (1/423; 0.2%); combinations of two or more of these drugs also resulted in substantial incidences of bleeding. The rates for minor GI bleeding in hospitalized patients varied from 8.3% for heparin to 1.6% for aspirin. In outpatients admitted because of serious GI bleeding, 14/88 (16%) had a history of heavy, regular aspirin use compared with 1,015/14,813 (6.9%) control subjects admitted for other reasons (relative risk, 2.1). No association between light regular use of aspirin and GI bleeding was noted. No association between the use of acetaminophen and GI bleeding was noted in any of the patients studied.

Acetaminophen↗
PubMed1990

Augmented gentamicin ototoxicity induced by vancomycin in guinea pigs.

Vancomycin has been reported to be an ototoxic drug in the clinical literature. At best, this literature is confusing. There are no reports of ototoxicity of vancomycin in experimental animals, even when it is administered concurrently with ethacrynic acid, a drug known to augment the ototoxic effect of most other ototoxic drugs. In most of the cases of permanent ototoxicity that have been reported, the patient was treated with an aminoglycoside antibiotic as well as vancomycin. This study found no evidence of vancomycin ototoxicity in guinea pigs, but found that vancomycin greatly enhanced the ototoxicity of gentamicin.

Acoustic Stimulation↗
PubMed2000

The influence of diet on the regional distribution of glutathione S-transferase activity in channel catfish intestine.

There is evidence that glutathione conjugates are the major metabolites formed following systemic uptake of carcinogenic contaminants from the intestine. The effect of commercial diet versus a semi-purified diet on the distribution of glutathione S-transferase (GST) activity was examined in proximal, medial, and distal sections of catfish intestine. The bulk of GST activity with 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and 3H-benzo[a]pyrene-4,5-oxide, and the percent cytosolic protein cross-reacting with anti-catfish GST-pi were in the more proximal segments and dropped off distally in the two diet groups. However, the total GST-pi cross-reacting protein in the proximal section was significantly higher in fish fed a chow diet. Western blot analysis revealed pi-class GST to be expressed principally in the proximal intestine. Cytosol samples cross-reacted with antibodies to human GST-alpha, -mu, and -pi, but not -theta, classes. Alpha-like GST isoforms of MW 26,200 and 24,600, absent in sections from fish fed a purified diet, were differentially expressed only in the distal section of chow-fed fish. These results indicate that diet significantly elicits regional differences in GST protein levels, that components of the commercial chow affect GST protein expression in the distal intestine, and that maintenance diet should be taken into consideration during dietary exposure studies.

Animals↗
PubMed1976

Regulation of active ion transport in the small intestine.

The epithelium of the small intestine can both actively absorb and actively secrete electrolytes and water. Secretion can be elicited in vitro by adding cyclic AMP or a stimulator of intestinal mucosal adenylate cyclase (cholera and Escherichia coli enterotoxins, prostaglandins, vasoactive intestinal peptide) or an inhibitor of cyclic AMP phosphodiesterase (theophylline). Cyclic AMP appears to alter intestinal ion transport at two different loci: it inhibits a coupled influx process for Na+ and Cl- at the luminal border, thereby reducing active absorption of NaCl, and it also stimulates the active secretion of anion (or Na+ and anion). A variety of evidence suggests that these two effects of cyclic AMP reside in different types of cells, the former in villus cells and the latter in crypt cells. The latter process is Na+-dependent and is inhibited by low concentrations of ouabain and ethacrynic acid. Active ion absorption in vitro can be enhanced by (1) stimulating Na+-coupled organic solute absorption with glucose, amino acids and possibly also oligo peptides; (2) reducing the HCO3- concentration and/or pH of the serosal bathing solution; and (3) introducing an alpha-adrenergic agonist. Cholera toxin-induced fluid production in vivo can be diminished by the first of these manoeuvres. The in vivo efficacies of the other two have not been evaluated.

Animals↗
PubMed1993

Mechanisms of drug resistance in ovarian cancer.

Alkylating agents, natural products and platinum complexes are the primary chemotherapeutic agents used in the treatment of patients with ovarian cancer. Resistance frequently develops to all three classes of drugs and can be functionally separated into distinct biochemical pathways: (1) relative dose intensity plays a role in resistance to platinum complexes and to a lesser degree with alkylating agents; (2) induction of the membrane P-170 glycoprotein confers resistance to natural products and due to the potential usefulness of Taxol (a natural product extracted from the bark of yew trees), this mechanism of resistance may become more clinically relevant in the future; (3) increased levels of cellular glutathione (GSH) and glutathione S-transferases are important in the detoxification of alkylating agents and platinum complexes; and (4) increased DNA repair also is characteristic of resistance to platinum complexes and alkylating agents. Clinical trials have been initiated with agents that may inhibit the biochemical mechanisms of acquired drug resistance. Clinical trials are already in progress with alkylating agents combined with inhibition of GSH biosynthesis (i.e., buthionine sulfoximine) or enzymatic inhibitors of glutathione S-transferase activity (i.e., ethacrynic acid). Furthermore, the combination of aphidicolin, an inhibitor of DNA repair, together with platinum complexes also soon will be clinically tested based on promising results in preclinical models of ovarian cancer. Ovarian cancer is a disease of the elderly. Advances in the pharmacology of platinum compounds and in our understanding of the mechanisms of drug resistance should permit these patients to receive increasingly more effective chemotherapy.

Alkylating Agents↗
PubMed2001

Suppression of GST-P by treatment with glutathione-doxorubicin conjugate induces potent apoptosis in rat hepatoma cells.

A conjugate of doxorubicin and glutathione via glutaraldehyde (GSH-DXR) inhibited glutathione S-transferase (GST) activity of rat hepatoma AH66 cells, and treatment of the cells with GSH-DXR induced caspase-3 activation and DNA fragmentation. After treatment of AH66 cells with 0.1 microM GSH-DXR, GST-P (placental type of rat GST isozymes) mRNA and its protein increased transiently and then decreased thereafter compared with the levels in nontreated cells. Caspase-3 activation and DNA fragmentation were induced following the suppression of GST-P expression by treatment with GSH-DXR. When the cells were treated with 100 microM ethacrynic acid (ECA), an inhibitor of GST, DNA fragmentation and caspase-3 activation were observed. In contrast, treatment of AH66 cells with a low concentration of ECA (1 microM) that showed little inhibition of GST activity induced slight, but significantly enhanced expression and activity of GST-P, and consequent prevention of DXR- and GSH-DXR-induced DNA fragmentation. Overexpression of GST-pi (placental type of human GST isozymes) by transfection of GST-pi sense cDNA into AH66 cells decreased sensitivities to DXR and GSH-DXR, and the suppression of GST-P by transfection of the antisense cDNA into the cells increased drug sensitivity. On the other hand, there was little change in drug sensitivity caused by overexpression of site-directedly mutated GST-P in which the active-site residue Tyr39 was replaced with His (W39H) or the substrate-binding site residue Cys48 was replaced with Ser (C48S) by transfection of those cDNAs into AH66 cells. These results suggested that the suppression of GST-P in AH66 cells treated with GSH-DXR must play an important role in the induction of apoptosis.

Animals↗
PubMed1994

Characterization of a human bladder cancer cell line selected for resistance to mitomycin C.

This study describes characteristics of a human bladder cancer cell line J82/MMC that is 6-fold more resistant to mitomycin C (MMC) than the parental cells. The J82/MMC subline was isolated by repeated continuous exposures of the J82/WT cells to increasing concentrations of MMC. The J82/MMC cell line showed (1) collateral sensitivity to taxol, 5-FU and topoisomerase II inhibitors; and (2) cross-resistance to cisplatin, melphalan and MMC analogues BMY 25282 and BMY 25067. Levels of two key MMC activation enzymes, NADPH cytochrome P450 reductase and DT-diaphorase, were significantly lower in J82/MMC cells compared with J82/WT, suggesting that lower sensitivity of J82/MMC cells to MMC may result from deficient drug activation. Further support is indicated by: 1) reduction in the differential in toxicity between the 2 cell lines by BMY 25282; and 2) a higher effect of DT-diaphorase inhibitor dicumarol on the wild-type cells compared with J82/MMC. Although glutathione (GSH) levels did not differ in these cells, a small but significant increase in GSH transferase (GST) activity was noticed in J82/MMC cells. GST inhibitor ethacrynic acid significantly enhanced MMC cytotoxicity in the J82/MMC cell line. A small but significant increase in the level of anti-oxidative enzyme catalase, but not GSH peroxidase, was also observed in J82/MMC cell line compared with J82/WT. Thus, the possibility that relatively lower sensitivity of J82/MMC cells to MMC may result from reduced oxygen radical generation cannot be ruled out. MMC-induced DNA interstrand cross-linking was markedly lower in the J82/MMC cell line compared with J82/WT. Our results suggest that the MMC resistance in the J82/MMC cell line may be multifactorial.

Antineoplastic Agents↗
PubMed1994

DT-diaphorase as a determinant of sensitivity to adriamycin in non-small-cell lung-cancer cell lines.

We have reported the establishment of a mitomycin-C (MMC)-resistant non-small-cell lung-cancer cell line, PC-9/MC4. As determined by an MTT assay, this resistant cell line was found to be 4 times more sensitive to adriamycin (ADM) than was the parental PC-9. There were no significant differences in sensitivity to etoposide, mitoxantrone, daunomycin, epirubicin, pirarubicin, 9-aminoanthracycline or 3'-deamino-3'-morpholino-13-deoxo-10-hydroxy carminomycin. These data suggest that neither qualitative or quantitative changes in DNA topoisomerase II nor the enhanced repair of DNA can explain the differing sensitivity to ADM observed. No significant differences were found in the accumulation of ADM and glutathione (GSH) in these cell lines. Although total glutathione-S-transferase (GST) activity in PC-9/MC4 cells was lower than that observed in PC-9 cells and treatment with ethacrynic acid (EA) reduced sensitivity to ADM in both cell lines, relative resistance was unaffected. NADH-cytochrome b5 reductase (B5R) activity in PC-9/MC4 cells showed a 3-fold greater decrease than that in PC-9 cells, and DT-diaphorase (DTD) activity in PC-9/MC4 cells showed an approximately 200-fold greater decrease than that in PC-9 cells. Addition of dicumarol, an inhibitor of DTD, decreased the sensitivity of ADM of PC-9 but not of PC-9/MC4. DTD activity in the PC-9 cell line was inhibited by treatment with dicumarol while in PC-9/MC4 it remained unchanged. These data suggest that DT-diaphorase is a determinant of sensitivity to ADM in the 2 cell lines.

Adenocarcinoma↗
PubMedDate not supplied

Factors moderating the effect of oral sulfonylureas on free water clearance.

The effects of the antidiuretic agent chlorpropamide and the diuretic agent tolazamide on solute-free water clearance (CH2O) were compared in noninsulin-dependent diabetic patients undergoing water diuresis. Hyperglycemia (fasting serum glucose above 200 mg/dl) obscured the effects of these two sulfonylureas on CH2O. Thiazide or ethacrynic acid enhancement of chlorpropamide antidiuresis was also blunted by hyperglycemia and attendant osmotic diuresis. Thus, the low incidence of symptomatic hyponatremia during chlorpropamide treatment of diabetic patients may be explained by persistent hyperglycemia in such patients.

Aged↗
PubMed1982

Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin.

It is known that nonsteroidal antiinflammatory drugs such as indomethacin can attenuate the pharmacologic effect of loop diuretics such as furosemide and ethacrynic acid and that indomethacin may also reduce the pharmacologic response to chlorothiazide. To examine further this potential drug-drug interaction, we administered 50- an 100-mg single oral doses of hydrochlorothiazide with and without indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin either on the pharmacokinetics of hydrochlorothiazide or the pharmacologic response to this diuretic. The adsorption and disposition of hydrochlorothiazide demonstrate that this drug is rapidly absorbed and produces a diuretic and natriuretic response that peaks at approximately 2 hours after dosing and is essentially terminated 12 hours after dosing. There appeared to be no greater pharmacologic response to the 100-mg than to the 50-mg hydrochlorothiazide dose in the ten subjects in this study.

Adult↗
PubMed1977

Noxious effects upon cochlear metabolism.

The influence of various toxic substances and of drugs with ototoxic side effects upon energy generation, energy utilization, and membrane processes of the cochlea were studied. None of the drugs tested interfered with energy generation to as great an extent as did anoxia or cyanide and 2,4-dinitrophenol. Ouabain produced a pronounced interference with energy utilization of the stria vascularis. The "loop" diuretics ethacrynic acid and furosemide produced a reduction of energy utilization of a lesser degree than did ouabain. The "loop" diuretics do not seem to exert their toxic action upon strial Na+K+-ATPase, but may act by interfering with strial adenylate cyclase. Aminoglycoside antibiotics and diuretic and nondiuretic mercurials seem to exert their primary noxious action upon cochlear function by interfering with membrane processes of the structures bounding the cochlear duct.

Action Potentials↗
PubMed2004

The interaction of selected natural products with human recombinant glutathione transferases.

The interaction of geshoidin, diospyrin and ergothioneine, with heterologously expressed human glutathione transferases (GSTs) was investigated in vitro. Diospyrin and geshoidin inhibited the three GST isoforms tested, with IC50 values in the range 0.1-0.5 microm, whereas ergothioneine had no effect on the GSTs. The predominant mode of inhibition was noncompetitive with respect to both glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). Diospyrin, however, competitively inhibited A1-1 and M1-1 with respect to GSH and geshoidin displayed mixed inhibition toward A1-1 with respect to GSH. The Ki values for diospyrin with respect to both GSH and CDNB were in the range 0.08-0.6 microM and those for geshoidin were in the range 16-173 microM. These results indicate that diospyrin is a potent inhibitor of heterologously expressed human GSTs A1-1, M1-1 and P1-1. Diospyrin and geshoidin were also found to inactivate P1-1 with diospyrin being a potent inactivator. Given these inhibitory properties, diospyrin may be a potential GST chemomodulator. Ergothioneine inactivated P1-1 only after preincubation and it enhanced ethacrynic acid inactivation of P1-1. Inactivation of P1-1 by ergothioneine may have implications for the antioxidant roles of P1-1 and ergothioneine in vivo.

Dose-Response Relationship, Drug↗
PubMed1993

Denitrosation of the anti-cancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea catalyzed by microsomal glutathione S-transferase and cytochrome P450 monooxygenases.

The alkylating agent BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] can be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes. While previous studies have identified a class mu glutathione S-transferase [rat transferase 4-4 (Yb2)] as a major catalyst of the cytosolic denitrosation reaction, the enzymatic catalysts of BCNU denitrosation in microsomal membranes have not been identified. In the present study, both NADPH and glutathione (GSH) were found to support BCNU denitrosation catalyzed by isolated rat liver microsomes. Treatment of rats with the microsomal enzyme inducers phenobarbital and dexamethasone increased NADPH-dependent liver microsomal BCNU denitrosation up to fivefold without major effect on the GSH-dependent denitrosation activity. Although the NADPH-dependent activity was fully inhibited by antibody to NADPH-P450 reductase, purified NADPH-P450 reductase catalyzed BCNU denitrosation at rates that could only account for approximately 2-3% of the microsomal activity. Other experiments, including selective inhibition of NADPH-dependent microsomal BCNU denitrosation by chemical and antibody inhibitors of cytochrome P450, competitive inhibition of P450-catalyzed cyclophosphamide and ifosfamide activation by BCNU, and reconstitution of the denitrosation reaction by purified P450 enzyme 2B1 (major phenobarbital-inducible P450 form), established an important role for cytochrome P450 in BCNU denitrosation. By contrast, GSH-dependent microsomal BCNU denitrosation was unaffected by cytochrome P450 inhibitors, but was inhibited, with varying degrees of selectivity, by the microsomal glutathione S-transferase inhibitors ethacrynic acid, bromosulfophthalein, and indomethacin. These studies establish that BCNU inactivation can be catalyzed by two independent microsomal enzyme systems and suggest that therapeutically useful improvements in BCNU antitumor activity might be achieved through differential inhibition of these enzyme systems in tumor as compared to extratumoral sites.

Animals↗
PubMed1994

Purification and kinetic mechanism of the glutathione S-transferase from C6/36, an Aedes albopictus cell line.

Glutathione S-transferase from an Aedes albopictus cell line, C6/36, was purified to apparent homogeneity by a single glutathione-Sepharose 4B affinity chromatography, with an overall yield of 66% and 226-fold purification. The enzyme is presumably a homodimer with subunit M(r) 23,000, which is similar to the enzyme isolated from other sources. Under native conditions, the enzyme exhibited multiple forms upon isoelectric focusing or polyacrylamide gel electrophoresis, and all these forms retained enzymatic activity. The pI value of the purified enzyme was distributed between approximately 4.7 and 5.4 with major form at 4.9. The purified enzyme lost 63% activity at -20 degrees C within 1 week. Stability of the purified enzyme was greatly improved by the addition 10 mg/ml of bovine serum albumin, under which only 7% activity was lost after 1 week at -20 degrees C. Activation energy for the enzyme-catalyzed conjugation of glutathione with 1-chloro-2,4-dinitrobenzene was found to be 49.1 kJ/mol. The enzyme could utilize 1-chloro-2,4-dinitrobenzene and ethacrynic acid as substrate, but not bromosulfophthalein, cumene hydroperoxide, or trans-4-phenyl-3-buten-2-one. The initial-velocity and product-inhibition studies indicated that the enzyme reaction conformed to a steady-state random Bi-Bi kinetic mechanism, which was similar to the glutathione S-transferase from other sources. The kinetic data also indicated a synergistic effect between the binding of glutathione G-site and that of organic electrophilic substrate in the H-site of the enzyme active center. The biological significance of the conjugation reaction is discussed.

Aedes↗
PubMed1999

Inhibition of antioxidants and hyperthermia enhance bleomycin-induced cytotoxicity and lipid peroxidation in Chinese hamster ovary cells.

Regional hyperthermia has potential for human cancer treatment, particularly in combination with systemic chemotherapy or radiotherapy. Heat enhances the cytotoxic effect of certain anticancer agents such as bleomycin, but the mechanisms involved in cell killing are currently unknown. Bleomycin generates reactive oxygen species. It is likely that hyperthermia itself also increases oxidative stress in cells. We evaluate whether oxidative stress has a role in the mechanism of cell death caused by bleomycin and heat in Chinese hamster ovary cells. Heat (41 to 44 degrees C) increased cytotoxicity of bleomycin, evaluated by clonogenic cell survival. Decreased levels of cellular antioxidants should create an imbalance between prooxidant and antioxidant systems, thus enhancing cytotoxic responses to heat and to oxidant-generating drugs. We determine the involvement of four major cellular antioxidant defenses, superoxide dismutase (SOD), the glutathione redox cycle (GSH cycle), catalase, and glutathione S-transferase (GST), in cellular sensitivity to bleomycin, alone or combined with hyperthermia. These cellular defenses were inhibited by diethyldithiocarbamate, l-buthionine sulfoximine, aminotriazole, and ethacrynic acid, respectively. We show that levels of antioxidants (SOD, GSH cycle, and GST) affect cellular cytotoxic responses to bleomycin, at normal and elevated temperatures (41 to 44 degrees C), suggesting the involvement of oxidative stress. Bleomycin and iron caused oxidative damage to membrane lipids in intact cells, at 37 and 43 degrees C. Lipid peroxidation was evaluated by fluorescence detection of thiobarbituric acid-reactive products. There was an increase in damage to membrane lipids when the antioxidant defenses, SOD and catalase, were inhibited. The differing effects of antioxidant inhibitors on bleomycin-induced cytotoxicity and membrane lipid damage suggest that different mechanisms are involved in these two processes. However, free radicals appear to be involved in both cases. The marked sensitization of cells by diethyldithiocarbamate, to both bleomycin-induced cytotoxicity and lipid peroxidation, suggests that superoxide could be involved in both of these processes.

Animals↗
PubMed1993

Enhanced glutathione S-transferase 7-7 expression in rat hepatic cytosol following treatment with pyrrole.

Rat hepatic GST 7-7 expression in cytosol and in the S-hexylglutathione-agarose affinity purified fraction of cytosol from saline- (control) and pyrrole-treated animals was examined using metabolic activity, SDS-PAGE, immunoblot, and HPLC analyses. Metabolic activity of hepatic cytosol from pyrrole-treated animals was assayed using the substrates 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and acrolein, and an approximately 1.5-, 1.2-, and 1.3-fold increase, respectively, was monitored in the rate of GST-catalyzed substrate conjugation to reduced glutathione. SDS-PAGE and immunoblot analysis using Class Pi GST-specific IgG confirmed that the GST 7 subunit was expressed in hepatic cytosol and in the affinity purified fractions from pyrrole-treated rats. In contrast, the GST 7 subunit was below the limit of detection in hepatic cytosol of saline-treated animals. HPLC analysis demonstrated the presence of the GST 7 subunit in the affinity purified fraction from pyrrole-treated rat hepatic tissue and showed that the level of this subunit was increased approximately 8-fold relative to the barely detectable level present in control tissue. N-terminal amino acid sequencing analysis confirmed the identity of the HPLC peak as GST 7-7. GST subunits 3, 1a, and 1b were elevated approximately 1.7-, 2.0-, and 2.4-fold respectively, in response to pyrrole treatment. These data provide evidence that pyrrole treatment results in de novo expression of GST 7-7 in rat hepatic tissue and suggest that pyrrole-containing compounds potentially generated during disease and/or altered heme metabolism, or those ingested in food products, may alter GST expression in hepatic tissue.

Animals↗
PubMed1997

Schistosoma japonicum GSH S-transferase Sj26 is not the molecular target of praziquantel action.

It has been suggested that Sj26, a Schistosoma japonicum GSH S-transferase, is the molecular target of the antischistosomal drug praziquantel (McTigue et al., 1995, J. Mol. Biol. 246, 21-27). We tested this hypothesis by asking two questions: (1) does praziquantel inhibit Sj26 activity with a variety of model substrates; and (2) does praziquantel prevent the binding to Sj26 of physiologically relevant nonsubstrate ligands? High concentrations of praziquantel (up to 500 microM) did not inhibit Sj26 activity using the model substrates 1-chloro-2,4-dinitrobenzene, 3,4-dichloronitrobenzene, or ethacrynic acid. Sj26 had no measurable activity with two higher molecular weight GSH S-transferase substrates: 5-androsten-3,17-dione and sulfobromophthalein. We also assessed the ability of praziquantel to prevent the inhibition of Sj26 by a series of S-alkyl-GSH conjugates. The half-maximal inhibitory concentrations of S-hexyl-GSH, S-octyl-GSH, and S-decyl-GSH (10, 10, and 5 microM, respectively) for Sj26 were not affected by up to 500 microM praziquantel. This suggests that praziquantel does not compete with GSH for Sj26 binding. In order to determine if praziquantel disrupts binding of nonsubstrate ligands to Sj26, we tested praziquantel for its ability to prevent the inhibition of Sj26 by both bilirubin and hematin. Praziquantel (100 or 500 microM) did not alter inhibition of Sj26 by 3 microM bilirubin, but partially protected Sj26 against inhibition by hematin (0.1 to 2.0 microM). Interestingly, in a similar reaction, 100 microM S-methyl-GSH protected Sj26 from inhibition equally as well as praziquantel. Bovine serum albumin (5 microM) completely protected against inhibition by 1 microM hematin. These results indicate that although praziquantel partially protects Sj26 from hematin inhibition, this protection is neither specific to praziquantel nor physiologically relevant. Our results do not support the hypothesis that the mechanism of praziquantel action involves competitive inhibition of Sj26 catalytic activity or blocking binding of nonsubstrate ligands. We can, therefore, find no evidence that Sj26 is the molecular target of the antischistosomal activity of praziquantel.

Animals↗
PubMed1995

In vitro acrylamide exposure alters growth cone morphology.

Acrylamide intoxication leads to degeneration of the longest axons of the central and peripheral nervous systems in humans and laboratory animals. Axonal derangements resulting from in vivo acrylamide exposure are first noted within synapses of the longest axons before involving more proximally located axonal segments or shorter axons, thus illustrating the specificity of acrylamide for the terminal axonal regions. As a possible model system for investigating the mechanism of toxicity of acrylamide on the distal axon, we exposed neurite-extending chick dorsal root ganglion (DRG) cells to acrylamide in vitro and then examined growth cones for alterations in morphology and function. Exposing DRG explants to media containing from 0.125 to 1.0 mM acrylamide for 16 hr leads to specific and dose-responsive alterations of growth cone morphology including: a nearly total loss of filopodial elements, the preservation of highly active but two-dimensional lamellar structures, an inappropriate extension of the axonal cytoskeleton into the forward region of most growth cones, and a frequent breakdown of the central and peripheral growth cone domains. The sulfhydryl alkylating agents ethacrynic acid, iodoacetamide, and iodoacetic acid were tested and none produced acrylamide-like morphological alterations at any dose. DRG cultures were also exposed to the neurotoxic acrylamide analogs glycidamide, N-hydroxy-methacrylamide (HM-ACR), and methacrylamide (M-ACR). At concentrations of 0.25 to 1.0 mM, glycidamide exposure resulted in acrylamide-like growth cone alterations. HM-ACR exposure also resulted in growth cones that were acrylamide-like but only at concentrations > 1.5 mM. M-ACR did not produce acrylamide-like growth cones at doses of up to 16.6 mM. Thus, in vitro exposure of DRG explants to acrylamide and two neurotoxic acrylamide analogs leads to reproducible and specific morphological alterations that are dose-dependent and separable from the effects of sulfhydryl alkylation.

Acrylamide↗