Biomedical subjects

S Y Lin-Shiau

Publications and source records attributed to S Y Lin-Shiau.

At least 19 recordsLinked to original sources

PubMed2001

Toxic effects of potassium bromate and thioglycolate on vestibuloocular reflex systems of Guinea pigs and humans.

Potassium bromate (KBrO(3)) and thioglycolate are two components of hair curling solution. The neurotoxic effects of KBrO(3) and thioglycolate on the vestibuloocular reflex (VOR) system have not been elucidated. In this paper, we report the adverse effects of KBrO(3) and thioglycolate on the VOR system of Hartley-strain guinea pigs. The function of the VOR system was evaluated by caloric test coupled with the electronystagmographic recordings after subcutaneous injection of 20 or 50 mg/kg KBrO(3) or 15 mg/kg thioglycolate, either alone or in combination once daily for 14 consecutive days. The results showed that KBrO(3) produced abnormal caloric responses in a concentration-dependent manner and thioglycolate enhanced this abnormality. Our clinical patients, 10 female hairdressers exposed to the hair curling solution for 10-30 years revealed a similar dysfunction in the caloric test. The possible mechanism of this adverse effect was studied: the cerebellar-regulated functions such as motor equilibrium performance and spontaneous locomotor activity of guinea pigs were reduced, the enzymatic Na(+)/K(+)-ATPase and Ca(2+)-ATPase activities of cerebellar tissues were significantly decreased, and the loss of Purkinje cells as well as the derangement of the granular cell layer of the cerebellar cortex was revealed after treatment with KBrO(3) plus thioglycolate. These findings imply that KBrO(3) plus thioglycolate is toxic to the VOR system, mediated by, at least in part, the dysfunction of a higher cerebellar regulatory mechanism. We suggest that the caloric test is a noninvasive method for monitoring the consequences of hazardous exposure of hair curling solution in humans. Our clinical findings together with the animal study imply that clinicians should be alert to the risk of bromate exposure in hairdressers, especially those with vertigo, tinnitus, or hearing loss.

Adenosine Triphosphatases↗

PubMed2001

Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator-activated receptor-gamma by flavonoids in mouse macrophages.

Peroxisome proliferator-activated receptor (PPAR)gamma transcription factor has been implicated in anti-inflammatory response. Of the compounds tested, apigenin, chrysin, and kaempferol significantly stimulated PPAR gamma transcriptional activity in a transient reporter assay. In addition, these three flavonoids strongly enhanced the inhibition of inducible cyclooxygenase and inducible nitric oxide synthase promoter activities in lipopolysaccharide-activated macrophages which contain the PPAR gamma expression plasmids. However, these three flavonoids exhibited weak PPAR gamma agonist activities in an in vitro competitive binding assay. Limited protease digestion of PPAR gamma suggested these three flavonoids produced a conformational change in PPAR gamma and the conformation differs in the receptor bound to BRL49653 versus these three flavonoids. These results suggested that these three flavonoids might act as allosteric effectors and were able to bind to PPAR gamma and activate it, but its binding site might be different from the natural ligand BRL49653.

Animals↗

PubMed2001

Abnormal auditory brainstem responses for mice treated with mercurial compounds: involvement of excessive nitric oxide.

In this paper, we attempted to construct an animal (mouse) model for monitoring the oto-neurotoxicity of mercuric sulfide, comparing its toxicity with the well-known (organic) mercury compound methyl-mercury. Mice were treated with either mercuric sulfide (HgS, 0.1 and 1.0 g/kg per day) or methyl-mercury (MeHg, 0.2, 2.0 and 10 mg/kg per day) by gastric gavage for 7 consecutive days. Analysis of auditory brainstem response (ABR) indicated that significant elevation of the physiological hearing threshold as well as significant prolongation of interwave latency I-V was observed for MeHg -- (2.0 and 0.2 mg/kg per day) or HgS -- (1.0 g/kg per day, but not 0.1 g/kg per day) treated mice. Further, both MeHg- and HgS-treated animals demonstrated a significant prolongation of interwave latency I-V that increased with an increasing mean blood-Hg level. The oto-neurotoxicity of MeHg (2.0 mg/kg per day) persisted to at least 11 weeks subsequent to the cessation of its administration. The toxic effect of HgS, however, disappeared completely 5 weeks subsequent to the cessation of its administration. These results suggest a correlation between the Hg-elicited hearing dysfunction and the availability of mercury in brain tissue. Both inhibition of Na(+)/K(+)-ATPase activity and overproduction of nitric oxide in the brainstem are consistent with an analysis of the physiological hearing threshold and latencies of ABR waveform at all time points throughout the experimental process. Thus, it is proposed that high-dose HgS or MeHg intoxication is associated with a decrease in functional Na(+)/K(+)-ATPase activity in the brainstem of affected animals, this presumably arising via excessive nitric oxide production, and suggesting that brainstem damage may play a role in mercury-induced hearing loss.

Animals↗

PubMed2001

Oxidative stress and c-Jun-amino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu(2+) complex.

Disulfiram is frequently used in the treatment of alcoholism. In this study, we found that CuCl(2) (1-10 microM), but not other metal ions (Fe(2+), Zn(2+), Pb(2+)), markedly potentiated disulfiram-induced cytotoxicity by 440-fold in primary astrocytes. Thus, the molecular mechanisms of the cytotoxic effects induced by the disulfiram-Cu(2+) complex were explored. The changes in morphology (nuclear condensation and apoptotic body formation) and hypodiploidy of DNA suggested that the disulfiram-Cu(2+) complex induced an apoptotic process. Our studies of the death-signaling pathway reveal that decreased mitochondrial membrane potential, increased free radical production, and depletion of non-protein-thiols (glutathione) were involved. The disulfiram-Cu(2+) complex activated c-Jun-amino-terminal kinase (JNK) and caspase-3 followed by poly (ADP-ribose) polymerase degradation in a time-dependent manner. Moreover, the cellular Cu content was markedly increased and the copper chelator bathocuproine disulfonate abolished all of these cellular events, suggesting that Cu(2+) is essential for death signaling. The antioxidants N-acetylcysteine and vitamin C also inhibited the cytotoxic effect. Thus, we conclude that the disulfiram-Cu(2+) complex induces apoptosis and perhaps necrosis at a late stage mediated by oxidative stress followed by sequential activation of JNK, caspase-3 and poly (ADP-ribose) polymerase degradation. These findings imply that the axonal degeneration and neurotoxicity observed after the chronic administration of disulfiram are perhaps, at least in part, due to the cytotoxic effect of the disulfiram-Cu(2+) complex formed endogenously.

Animals↗

PubMed2001

Neurotoxicity of mercury sulfide in the vestibular ocular reflex system of guinea pigs.

A traditional Chinese mineral medicine, cinnabar, naturally occurring mercuric sulfide (HgS), is still occasionally prescribed, but the neurotoxic effects of HgS have not been elucidated. In this paper, an animal model of the purified HgS intoxication was established in guinea pigs in order to study neurotoxicity and pathophysiology of the vestibular ocular reflex system (VOR). Guinea pigs were dosed with HgS by gastric gavage (0.01, 0.1 and 1.0 g/kg per day) for 7 consecutive days. By means of caloric testing coupled with the electronystagmographic (ENG) recording in guinea pigs, we have found that HgS at a dose of 0.1 g/kg induced reversible caloric hypofunction pattern and at a higher dose of 1.0 g/kg induced irreversible hypofunction of caloric test. Monitoring the mercury contents of various tissues (blood, kidney, liver and cerebellum) by continuous flow and cold vapor atomic absorption spectrometry (AAS) revealed that a certain amount of HgS could be absorbed from the gastrointestinal tract and was detectable in these tissues. In addition to the induced dysfunction of VOR system, HgS also caused disturbance of motor performance in guinea pigs. In enzyme assay, Na+/K+-ATPase activity of cerebellum was also significantly inhibited by HgS. Morphological studies showed partial cell loss only in the cerebellar Purkinje cell layer, but not in the granule cell layer, nor in the vestibular labyrinth. All of these findings suggest that cerebellar Purkinje cells are the sensitive target site responsible for HgS-inducing dysfunctions of both VOR system and the motor performance in guinea pigs. Thus, it is concluded that caloric test coupled with ENG recording in VOR system is certainly a sensitive biomarker for monitoring the neurotoxicity of HgS.

Analysis of Variance↗

PubMed2001

Suramin prevents cerebellar granule cell-death induced by dequalinium.

In this study, we demonstrated that an anticancer drug, dequalinium, a bisquaternary ammonium compound, is a potent neurotoxicant with IC(50) of 0.46 microM on the cultured cerebellar granule neurons. Its selective neurotoxicity revealed by 100-fold more toxic than the other two analogs, pancuronium and vecuronium. The mechanisms underlying dequalinium (DQ)-induced neurotoxicity were explored and found to be associated with decreased mitochondrial membrane potential, increased free radical production and ATP depletion. Suramin (a nonselective purinergic P(2) receptor antagonist and an anticancer drug) but not the glutamate receptor antagonists, MK-801, NBQX (1,2,3,4 tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium), and DNQX (6,7-dinitroquinoxaline-2,3-dione) significantly prevents the DQ-induced neurotoxicity. By means of microfluorometric image-processing technique using the fluorescent probes, fluorescein diacetate/propidium iodide and Hoechst 33258, respectively, we showed that 1 microM DQ for 24 h induced about 53.5% of apoptosis and 37.5% of necrosis. All of these effects of DQ can be completely prevented by suramin. From these results, we conclude that DQ-induced neurotoxicity was not mediated by glutamate receptor, but by increasing free radical productions and cell energy depletion. Suramin with its beneficial antagonistic effects on DQ-induced neurotoxicity may provide an effective approach for neurodegeneration.

Adenosine Triphosphate↗

PubMed2001

Effects of gentamicin and pH on [Ca2+]i in apical and basal outer hair cells from guinea pigs.

Aminoglycosides are widely used antibiotics and frequently produce acute ototoxicity. In this study we attempted to comparatively investigate the effects of gentamicin on Ca2+ influx of apical and basal outer hair cells (OHCs) isolated from guinea-pig cochlea. Since the solution of gentamicin sulfate salt is acidic (pH 3.1-3.3), we also explored the effect of external acidification on Ca2+ influx. By means of fura-2 microspectrofluorimetry, we measured the intracellular calcium concentration ([Ca2+]i) of OHCs bathed in Hanks' balanced salt solution (pH 7.40) during either a resting state or high K+-induced depolarization. Our results show that at the resting state, the baseline [Ca2+]i in apical OHCs (94+/-2.0 nM) was slightly lower than that in basal OHCs (101.1+/-2.4 nM). By contrast, the increase in [Ca2+]i evoked by high K+ depolarization in apical OHCs was about two-fold greater than that in basal OHCs. Nifedipine (30 microM) abolished the increased [Ca2+]i in both types of OHCs, suggesting that Ca2+ influx was mainly through L-type Ca2+ channels of OHCs. While gentamicin and extracellular acidification (pH 7.14) can separately attenuate this increase in [Ca2+]i in both types of OHCs, their suppressive effects are additive in basal OHCs, but not in apical OHCs. The implications of these findings are that: (1) apical and basal OHCs behave differently in response to depolarization-increased [Ca2+]i, and (2) basal OHCs are more vulnerable to the impairment of Ca2+ entry during depolarization by a combination of gentamicin and extracellular acidification, which is correlated with the clinical observation that ototoxicity of aminoglycosides at the basal coil of OHCs is more severe than that at the apical coils. Moreover, the possibility that extracellular acidification may enhance the acute ototoxic effects of aminoglycosides should be considered especially in topical applications.

Animals↗

PubMed2001

Na+,K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall following surgical induction of hydrops.

Na+,K+-ATPase and Ca2+-ATPase activities have not been studied quantitatively in the cochlea affected by endolymphatic hydrops. The present study was designed to measure quantitatively the Na+,K+-ATPase and Ca2+-ATPase activities in the cochlear lateral wall and the threshold of auditory brainstem response (ABR) for guinea pigs in the early stages (=2 months) of experimentally induced endolymphatic hydrops. A significant negative association was demonstrated between Ca2+-ATPase activity and the change in ABR threshold for hydropic cochleae (P=0.014), but not for control cochleae (P=0.123), although no such significant association was revealed between Na+,K+-ATPase activity and any change in ABR threshold for both hydropic cochleae (P=0.751) and control cochleae (P=0.352). A significant increase in Ca2+-ATPase activity in the cochlear lateral wall was observed for the hydropic ear, in which normal ABR thresholds were maintained, as compared to the control ear. On the contrary, a mild decrease in Ca2+-ATPase activity in the cochlear lateral wall was observed for the hydropic ear, in which ABR thresholds increased significantly. The present findings suggest that alterations of Ca2+-ATPase activity in the cochlear lateral wall may implicate disturbed calcium-homeostasis in the inner ear, resulting in hearing dysfunction in the early stages of experimentally induced endolymphatic hydrops.

Animals↗

PubMed2001

Potentiation of noise-induced hearing loss by amikacin in guinea pigs.

Noise and aminoglycosides initially attack cochlear outer hair cells (OHCs). Distortion product otoacoustic emissions (DPOAEs) are used for the early diagnosis of damage to OHCs. The effects of sub-damaging doses of amikacin, an aminoglycoside antibiotic agent, on noise-induced hearing loss (NIHL) were examined in guinea pigs. Animals were grouped by gender and exposed to broadband noise at 105 dB SPL for 12 h and/or injected i.m. with either amikacin (100 mg/kg/day) or saline for 10 days. Auditory brainstem response (ABR) thresholds, along with DPOAE amplitudes, were measured serially before and after noise exposure. DPOAE amplitudes decreased and ABR thresholds elevated immediately after noise exposure and then gradually recovered. At all frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by 4 days after noise exposure. There was no effect of amikacin on either the ABR threshold or DPOAE amplitudes, in animals treated with amikacin only. However, amikacin significantly prolonged the effect of noise exposure on DPOAE amplitude but not on the noise-induced temporary threshold shift (TTS) of the ABR. In animals treated with a combination of noise and amikacin, significant changes in DPOAE amplitudes were still observed at 4 weeks after cessation of noise exposure. No gender difference in the responses to noise and/or amikacin could be demonstrated. The present findings indicate that even sub-damaging dosages of amikacin might impair recovery from NIHL in guinea pigs.

Amikacin↗

PubMed2001

Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells.

Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC(50) values of 9.42 and 19.5 microM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.

Antineoplastic Agents↗

PubMed2001

Effects of methyl mercury, mercuric sulfide and cinnabar on active avoidance responses, Na+/K+-ATPase activities and tissue mercury contents in rats.

This study compared the neurobehavioral toxicities of three mercurial compounds: methyl mercury (MeHg) which is soluble and organic. and mercuric sulfide (HgS) and cinnabar (naturally occurring HgS), which are insoluble and inorganic. Cinnabar, a Chinese mineral medicine, is still used as a sedative in some Asian countries, but there is relatively little toxicological information about it. These mercurial compounds were administered intraperitoneally (MeHg, 2 mg/ kg) or orally (HgS and cinnabar, 1.0 g/kg) to male rats once every day for 13 consecutive days with assays conducted during or after discontinuous administration for 1 h, 2, 8 and 33 weeks. Neurotoxicity was assessed based on the active avoid-ance response and locomotor activity. The results obtained showed that MeHg and cinnabar prominently and irreversibly caused a decrease in body weight, prolongation of latency for escape from electric shock, a decrease in the percentage for the conditioned avoidance response (CAR) to electric shock, impairment of spontaneous locomotion and inhibition of Na+/K+-ATPase activity of the cerebral cortex. In contrast. HgS reversibly inhibited spontaneous locomotion and Na+/K+-ATPase activity. It was noted that HgS significantly decreased the latency of escape from electric shock during the ad-ministration period, which lasted for 33 weeks after discontinuous administration. In fact that pretreatment with arecoline (a cholinergic receptor agonist) but not fipexide (a dopaminergic receptor agonist) could significantly shorten the prolonged latency for escape caused by MeHg and cinnabar, suggested that the deficit in the active avoidance response was perhaps, at least in part, mediated by the dysfunction of the cholinergic rather than the dopaminergic system. Determination of the Hg levels of the whole blood and cerebral cortex revealed that the tissue mercury content was highly correlated with the degree of neurobehavioral toxicity of these Hg compounds. These findings suggest that insoluble HgS and cinnabar can be absorbed from the G-I tract and distributed to the brain. The possibility that contamination due to other minerals in the cinnabar is responsible for the greater neurotoxic effects compared to HgS is under investigation.

Animals↗

PubMed2001

Mechanisms of cancer chemoprevention by curcumin.

Curcumin is a major component of the Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and IkappaB kinase. In addition, curcumin inhibits the activation of NFkappaB and the expression of c-jun, c-fos, c-myc and iNOS. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently convened into monoglucuronide conjugates. The experimental results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice.

Animals↗

PubMed2000

Site of action of suramin and reactive blue 2 in preventing neuronal death induced by dequalinium.

Dequalinium (DQ, an anticancer drug) is a potent neurotoxicant in the cultured developing cerebellar granule neurons (CGNs) with an IC(50) of 1.31. M after 24 hr incubation. By utilizing fluorometric technique, we found that DQ initially induced apoptosis and then necrosis associated with a marked decrease in ATP contents. The purinergic P(2) receptor antagonists (suramin, and reactive blue 2) prevented DQ-cytotoxicity, although glutamate ionotropic receptor antagonists (MK 801 and NBQX) could not. Furthermore, we quantitatively determined a reduction of mitochondrial membrane potential and an increase of free radical production induced by DQ. Suramin abolished these detrimental events of DQ. This suggests that neuronal death induced by DQ is mediated, at least in part, through a signaling pathway of free radical production-mitochondrial dysfunction. Further evidence supporting this contention is that CGN progressively became more sensitive to both DQ-induced cytotoxicity and reduced mitochondrial membrane potential. This implies that neuronal mitochondria are apparently one of the target sites for DQ and suramin and directly or indirectly induce neurotoxicity and neuroprotection respectively. The alteration in mitochondrial membrane potential during neuronal maturation may be one of the determinants accounting for the increased susceptibility to neurotoxicants such as DQ.

Adenosine Triphosphate↗

PubMed2000

Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages.

Nitric oxide (NO) plays an important role in inflammation and in the multiple stages of carcinogenesis. In this study, we investigated the inhibitory effects of curcumin and its metabolites, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin, on the induction of NO synthase (NOS) in RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and northern blotting analyses demonstrated that curcumin strongly reduced 130-kDa protein and 4.5-kb mRNA levels of iNOS in LPS-activated macrophages compared with its metabolites, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that curcumin blocked the LPS-induced binding of nuclear factor-kappaB (NFkappaB), a transcription factor necessary for iNOS induction to its (32)P-labeled double-stranded oligonucleotide probe. The inhibition of NFkappaB activation occurred through the prevention of inhibitor kappaB (IkappaB) degradation. Transient transfection experiments also showed that curcumin inhibited NFkappaB-dependent transcriptional activity. Curcumin blocked the disappearance of inhibitory kappaBalpha (IkappaBalpha) and p65 from the cytosolic fraction, and inhibited the phosphorylation of IkappaBalpha. Furthermore, we showed that curcumin could inhibit the IkappaB kinase 1 (IKK1) and IkappaB kinase 2 (IKK2) activities induced by LPS, but tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin were less active. These results suggest that curcumin may exert its anti-inflammatory and anti-carcinogenic properties by suppressing the activation of NFkappaB through inhibition of IKK activity.

Animals↗

PubMed2000

Activation of transcription factors of nuclear factor kappa B, activator protein-1 and octamer factors in hyperalgesia.

Involvement of c-fos and neuronal nitric oxide synthase (nNOS) in the hyperalgesia induced by complete Freund adjuvant (CFA) has been reported. In this paper, we attempted to investigate whether the transcription factors regulating the gene expression of c-fos and nNOS, including activator protein-1 (AP-1), nuclear factor kappa B (NF-kappa B), and octamer factors (Oct), are activated by CFA during the development of hyperalgesia. The electrophoretic mobility shift assay (EMSA) was used to determine whether there were changes in the transcription factors in the lumbar spinal cord of adult rats following subcutaneous injection of CFA in one hindpaw of the rats. Maximum binding of AP-1, NF-kappa B and Oct was found at 0.5, 1 and 2 h after CFA injection, respectively. These findings suggest that the activation of these transcription factors is pivotal for the expression of c-Fos and nNOS proteins, which reached a peak at 3 and 48 h after CFA injection, respectively. The behavioral testing of hyperalgesia demonstrated that CFA reduced the thresholds for mechanical and thermal algesia, reaching a minimum at 6 h. The thresholds had only partially recovered after 96 h. Based on these findings, we conclude that AP-1, NF-kappa B and Oct are crucial for the expression of c-Fos proteins at an early stage (at 3 h) and for the expression of nNOS at a late stage of hyperalgesia (48 h post-injection) induced by CFA.

Animals↗

PubMed2000

Nitration and hydroxylation of aromatic amino acid and guanine by the air pollutant peroxyacetyl nitrate.

Peroxyacetyl nitrate (PAN) is a common gaseous photochemical compound in polluted air and cigarette smog. The toxicity of PAN has been found to depend on three pathways: (1) its oxidizing property that mimics peroxide or peroxynitrite; (2) its nitrating and hydroxylating properties similar to peroxynitrite; and (3) its acetylating property like acetic anhydride. The present investigations were intended to focus on the reactions of PAN with aromatic amino acids and guanine. When PAN interacted with tyrosine and guanine the major products were 3-nitrotyrosine, 3, 5-dinitrotyrosine, 8-hydroxyguanine and 8-nitroguanine. These compounds have been used as indicators for the presence of peroxynitrite in previous studies. When PAN interacted with phenylalanine, the products were 3-nitrotyrosine, 4-nitrophenylalanine, p-tyrosine, o-tyrosine and m-tyrosine. 5-Hydroxytryptophan is produced from the reaction of PAN with tryptophan. Furthermore, the formation of nitrated tyrosines was also found in the PAN-treated HL-60 cells. A high yield of dityrosine was formed when PAN and peroxynitrite were reacted with tyrosine, probably through free radical oxidation. We also found that peroxynitrite and PAN are similar in their oxidizing activity. From these findings, we suggest that peroxynitrite may be considered as the reactive intermediate of PAN.

Air Pollutants↗

PubMed2000

The detrimental effects of potassium bromate and thioglycolate on auditory brainstem response of guinea pigs.

Potassium bromate (KBrO3) is known to be an oxidizing agent that is used not only as a food additive, mainly in the bread-making process, but also as a neutralizer in thioglycolate containing hair curling set. Although it has been shown that bromate poisoning could cause severe and irreversible sensorineural hearing loss as well as renal failure, the action mechanism of bromate-induced otoneurotoxicity especially its combination with thioglycolate remains to be studied. In this study, we attempted to investigate the toxic effects of KBrO3 in combination with or without thioglycolate on the auditory brainstem response (ABR) system in the guinea-pigs which was claimed to be very susceptible to the xenobiotics. In a preliminary test, we have found that after consecutive 2 weeks administration, KBrO3 caused a significant prolongation of wave I-III and the interwave latencies of ABR as well as significantly elevated the threshold of hearing, suggesting that the conduction velocity of the peripheral auditory nerve was delayed. By contrast, the absolute latency of wave IV/V and the interwave latency of wave III-V were not significantly prolonged, suggesting that KBrO3 had no effect on the brainstem. This oto-neurotoxic effect of KBrO3 was markedly enhanced by combining with thioglycolate. Our data also indicated that KBrO3 combined with thioglycolate but not KBrO3 alone prominantly caused a decrease of body weight. However, enzymatic activities (including Na+/K+-ATPase and Ca2+-ATPase) and the level of nitric oxide (NO) was significantly affected in the brainstem. Based on these findings, we tentatively conclude that whether KBrO3 alone or KBrO3 combined with thioglycolate induced oto-neurotoxicity majorly through the peripheral auditory nerve rather than via the central brainstem intoxication.

Animals↗

PubMed2000

Suramin protects the murine motor nerves from the toxic effects of presynaptic Ca(2+) channel inhibitors.

The purpose of this study is to investigate whether suramin is capable of preventing the neurotoxic effects of Ca(2+) channel inhibitors at the presynaptic sites. Mouse diaphragm and triangularis sterni preparations were used for this study in order to measure the muscle tension and nerve terminal Ca(2+) current, respectively. Both omega-conotoxin MVIIC and omega-agatoxin IVA markedly inhibit the nerve-evoked muscle contractions as well as the nerve terminal Ca(2+) current respectively. Pretreatment with suramin (0.3 mM) significantly reduced the inhibitory effect of nerve-evoked muscle contractions and Ca(2+) current induced by either omega-conotoxin MVIIC or omega-agatoxin IVA but not that induced by the non-selective Ca(2+) channel blocker, Cd(2+). Neither suramin nor Ca(2+)-channel toxins significantly affect Na(+)- and K(+) currents of the nerve terminals. These findings indicate that suramin selectively interferes the action of presynaptic Ca(2+) channel neurotoxins and thus reduces their depressant effects on the muscle contractions. The implication of these findings is that suramin and its derivatives may potentially become useful agents in management of intoxication of Ca(2+) channel neurotoxins.

Animals↗