Serotonin-melatonin interactions in acetaminophen and N,N-dimethylformamide toxicity
- Anoopkumar-Dukie, Shailendra
- Authors: Anoopkumar-Dukie, Shailendra
- Date: 2000
- Subjects: Serotonin , Acetaminophen , Melatonin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3898 , http://hdl.handle.net/10962/d1003957 , Serotonin , Acetaminophen , Melatonin
- Description: Acetaminophen and N,N-dimethylformamide (DMF) are compounds which are extremely toxic to the liver. Acetaminophen is a drug which is well known for its analgesic and antipyretic properties. However, the abuse potential of this agent as a non-narcotic analgesic in alcoholics is well known. It is also the leading cause of overdose in England. DMF toxicity results mainly from occupational exposure. At present there are no known reports of an antidote for DMF poisoning, while N-acetylcysteine, the antidote for acetaminophen poisoning, is known to produce adverse effects. The present study evaluates the potential of melatonin as an antidote for acetaminophen and DMF poisoning. This study also investigates the mechanism underlying acetaminophen addiction and abuse. Initial studies involved in vitro techniques in an attempt to remove the complexities of organ interactions. The photodegradation studies, using ultraviolet (UV) light, revealed that melatonin accelerates the rate of acetaminophen degradation in the presence of air, and reduces the rate of degradation in the presence of nitrogen. This study also revealed that melatonin is rapidly degraded in the presence of air, following UV irradiation. The effect of DMF on hydroxyl radical generation was also determined. DMF was shown to act as a free radical scavenger, rather that a generator of free radicals. The in vitro studies were followed by lipid peroxidation determination. DMF (0.4ml/kg and 0.8ml/kg) did not produce any significant increases in lipid peroxidation in the liver. Three different doses of acetaminophen (30mg/kg, 100mg/kg, and 500mg/kg) were administered to rats for seven days. Acetaminophen (500mg/kg) was shown to significantly increase (p<0.05) lipid peroxidation in the liver. Melatonin (2.5mg/kg) was not able to significantly reduce the damage. The lower doses of acetaminophen (30mg/kg and 100mg/kg) did not increase lipid peroxidation. Electron microscopy studies showed that DMF adversely affects the liver, and in particular, the endoplasmic reticulum. Co administration of melatonin (2.5mg/kg) was able to reduce the damage. Further experiments need to be performed before an accurate assessment can be made on the ability of melatonin as an antidote for DMF and acetaminophen poisoning. Several experiments were done in an attempt to uncover the biochemical mechanism underlying acetaminophen addiction and abuse. The first experiment targeted the liver enzyme tryptophan-2,3-dioxygenase (TDO). This enzyme is the major determinant of tryptophan levels in vivo. Acetaminophen administration (100mg/kg for three hours) was shown to significantly inhibit (p<0.05) the activity of TDO, indicating increased peripheral levels of tryptophan. This experiment was followed up with determination of brain serotonin and pineal melatonin. Brain serotonin was determined using the ELISA technique. Melatonin was estimated using this technique as well as with pineal organ culture. Acetaminophen administration (100mg/kg for three hours) significantly increased (p<0.05) brain serotonin levels. Using organ culture where exogenous (3H) tryptophan is metabolised to (3H) melatonin, acetaminophen (100mg/kg for three hours) was shown to significantly increase (p<0.05) pineal melatonin concentrations. However, the ELISA technique did not reveal any changes in endogenous pineal melatonin levels. The final experiment was the determination of urinary 5-hydroxyindole acetic acid (5- HIAA), the major metabolite of serotonin, following acetaminophen administration (100mg/kg for three hours). Acetaminophen was shown to significantly reduce 5-HIAA levels (p<0.05) suggesting reduced catabolism of serotonin. The findings of this study indicate that acetaminophen mimics the actions of an antidepressant. This compelling finding has important clinical implications, and needs to be examined further.
- Full Text:
- Date Issued: 2000
- Authors: Anoopkumar-Dukie, Shailendra
- Date: 2000
- Subjects: Serotonin , Acetaminophen , Melatonin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3898 , http://hdl.handle.net/10962/d1003957 , Serotonin , Acetaminophen , Melatonin
- Description: Acetaminophen and N,N-dimethylformamide (DMF) are compounds which are extremely toxic to the liver. Acetaminophen is a drug which is well known for its analgesic and antipyretic properties. However, the abuse potential of this agent as a non-narcotic analgesic in alcoholics is well known. It is also the leading cause of overdose in England. DMF toxicity results mainly from occupational exposure. At present there are no known reports of an antidote for DMF poisoning, while N-acetylcysteine, the antidote for acetaminophen poisoning, is known to produce adverse effects. The present study evaluates the potential of melatonin as an antidote for acetaminophen and DMF poisoning. This study also investigates the mechanism underlying acetaminophen addiction and abuse. Initial studies involved in vitro techniques in an attempt to remove the complexities of organ interactions. The photodegradation studies, using ultraviolet (UV) light, revealed that melatonin accelerates the rate of acetaminophen degradation in the presence of air, and reduces the rate of degradation in the presence of nitrogen. This study also revealed that melatonin is rapidly degraded in the presence of air, following UV irradiation. The effect of DMF on hydroxyl radical generation was also determined. DMF was shown to act as a free radical scavenger, rather that a generator of free radicals. The in vitro studies were followed by lipid peroxidation determination. DMF (0.4ml/kg and 0.8ml/kg) did not produce any significant increases in lipid peroxidation in the liver. Three different doses of acetaminophen (30mg/kg, 100mg/kg, and 500mg/kg) were administered to rats for seven days. Acetaminophen (500mg/kg) was shown to significantly increase (p<0.05) lipid peroxidation in the liver. Melatonin (2.5mg/kg) was not able to significantly reduce the damage. The lower doses of acetaminophen (30mg/kg and 100mg/kg) did not increase lipid peroxidation. Electron microscopy studies showed that DMF adversely affects the liver, and in particular, the endoplasmic reticulum. Co administration of melatonin (2.5mg/kg) was able to reduce the damage. Further experiments need to be performed before an accurate assessment can be made on the ability of melatonin as an antidote for DMF and acetaminophen poisoning. Several experiments were done in an attempt to uncover the biochemical mechanism underlying acetaminophen addiction and abuse. The first experiment targeted the liver enzyme tryptophan-2,3-dioxygenase (TDO). This enzyme is the major determinant of tryptophan levels in vivo. Acetaminophen administration (100mg/kg for three hours) was shown to significantly inhibit (p<0.05) the activity of TDO, indicating increased peripheral levels of tryptophan. This experiment was followed up with determination of brain serotonin and pineal melatonin. Brain serotonin was determined using the ELISA technique. Melatonin was estimated using this technique as well as with pineal organ culture. Acetaminophen administration (100mg/kg for three hours) significantly increased (p<0.05) brain serotonin levels. Using organ culture where exogenous (3H) tryptophan is metabolised to (3H) melatonin, acetaminophen (100mg/kg for three hours) was shown to significantly increase (p<0.05) pineal melatonin concentrations. However, the ELISA technique did not reveal any changes in endogenous pineal melatonin levels. The final experiment was the determination of urinary 5-hydroxyindole acetic acid (5- HIAA), the major metabolite of serotonin, following acetaminophen administration (100mg/kg for three hours). Acetaminophen was shown to significantly reduce 5-HIAA levels (p<0.05) suggesting reduced catabolism of serotonin. The findings of this study indicate that acetaminophen mimics the actions of an antidepressant. This compelling finding has important clinical implications, and needs to be examined further.
- Full Text:
- Date Issued: 2000
Serotonin binding in vitro by releasable proteins from human blood platelets
- Authors: Heemstra, Valerie Lawrence
- Date: 1984 , 2013-04-10
- Subjects: Serotonin , Serotonin -- Metabolism
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3829 , http://hdl.handle.net/10962/d1007215 , Serotonin , Serotonin -- Metabolism
- Description: Among the substances released from human blood platelets are serotonin and various proteins. It was hypothesized that one of these proteins binds serotonin and that serotonin might be important to the protein's function or that the protein might be important to serotonin's function. Two platelet-specific proteins, platelet factor 4 (PF4) and ß-thromboglobulin ( ßTG) were found to bind serotonin in vitro. Endogenous PF4 was isolated by serotonin-affinity chromatography and was identified by radioimmunoassay. Purified l¹²⁵ I] -PF4 and native PF4 bound to and eluted from a serotonin-affinity column similarly. Ultrafiltration of the homologous protein, (ßTG, with [¹⁴C]-serotonin demonstrated binding of about 8 moles serotonin per mole tetrameric ßTG with a dissociation con stant of about 4 x 10-8ThesisThesis⁻⁸ M. Equilibrium dialysis of PF4 with radiolabelled serotonin was attempted, but no binding constant values were obtained because serotonin apparently bound to the dialysis membrane. Since EDTA was one of the two agents that eluted PF4 from the serotonin-affinity gel, calcium binding by -PF4 was investigated by equilibrium dialysis. Evidence was obtained for positively cooperative binding of calcium ions by PF4. It is concluded that PF4 and ßTG bind serotonin in vitro, that they may also bind in vivo when platelets undergo release, and that the functions of serotonin, PF4 and ßTG may be mediated in part by serotonin-protein associations. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 1984
- Authors: Heemstra, Valerie Lawrence
- Date: 1984 , 2013-04-10
- Subjects: Serotonin , Serotonin -- Metabolism
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3829 , http://hdl.handle.net/10962/d1007215 , Serotonin , Serotonin -- Metabolism
- Description: Among the substances released from human blood platelets are serotonin and various proteins. It was hypothesized that one of these proteins binds serotonin and that serotonin might be important to the protein's function or that the protein might be important to serotonin's function. Two platelet-specific proteins, platelet factor 4 (PF4) and ß-thromboglobulin ( ßTG) were found to bind serotonin in vitro. Endogenous PF4 was isolated by serotonin-affinity chromatography and was identified by radioimmunoassay. Purified l¹²⁵ I] -PF4 and native PF4 bound to and eluted from a serotonin-affinity column similarly. Ultrafiltration of the homologous protein, (ßTG, with [¹⁴C]-serotonin demonstrated binding of about 8 moles serotonin per mole tetrameric ßTG with a dissociation con stant of about 4 x 10-8ThesisThesis⁻⁸ M. Equilibrium dialysis of PF4 with radiolabelled serotonin was attempted, but no binding constant values were obtained because serotonin apparently bound to the dialysis membrane. Since EDTA was one of the two agents that eluted PF4 from the serotonin-affinity gel, calcium binding by -PF4 was investigated by equilibrium dialysis. Evidence was obtained for positively cooperative binding of calcium ions by PF4. It is concluded that PF4 and ßTG bind serotonin in vitro, that they may also bind in vivo when platelets undergo release, and that the functions of serotonin, PF4 and ßTG may be mediated in part by serotonin-protein associations. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 1984
The effect of tricyclic antidepressant drugs on the uptake and metabolism of serotonin by the pineal gland in organ culture
- Authors: Pillay, Manoranjenni
- Date: 1983 , 2013-04-05
- Subjects: Antidepressants , Pineal gland -- Metabolsim , Serotonin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3828 , http://hdl.handle.net/10962/d1007053 , Antidepressants , Pineal gland -- Metabolsim , Serotonin
- Description: The effect of tricyclic antidepressants (TADs) on a variety of pineal functions was assessed. TADs affected the uptake of ³H-5HT into bovine pineal slices within a particular concentration range of these drugs, DESI, CLOMI and IMI appeared to inhibit uptake slightly, within a limited concentration range. Surprisingly, DESI appeared to be a relatively potent 5HT uptake inhibitor. The 5-HT re-uptake system in the pineal probably differes from that in brain tissue. TADs had a marked effect on the metabolism of ³H-5HT in the rat pineal, in an organ culture system, MEL and N-acetylserotonin synthesis increased for the first 11 days and thereafter a slight decrease was observed. HTOH and HIAA also showed an initial increase followed by a slight decrease in synthesis. The synthesis of MTOH and MIAA was decreased. The possibility that TADs could affect HIOMT and SNAT synthesis and thereby change the metabolic pattern of 5-HT was investigated. TADs appeared to stimulate SNAT initially and thereafter a slight decrease from peak activity was observed. This is probably due to stimulation followed by development of subsensitivity of β-receptors, HIOMT activity also appeared to be affected by TADs. The existence of two types of HIOMT is suggested. There is a possibility that these changes in the metabolism of 5-HT could be implicated in the mechanism of action of TADs. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 1983
- Authors: Pillay, Manoranjenni
- Date: 1983 , 2013-04-05
- Subjects: Antidepressants , Pineal gland -- Metabolsim , Serotonin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3828 , http://hdl.handle.net/10962/d1007053 , Antidepressants , Pineal gland -- Metabolsim , Serotonin
- Description: The effect of tricyclic antidepressants (TADs) on a variety of pineal functions was assessed. TADs affected the uptake of ³H-5HT into bovine pineal slices within a particular concentration range of these drugs, DESI, CLOMI and IMI appeared to inhibit uptake slightly, within a limited concentration range. Surprisingly, DESI appeared to be a relatively potent 5HT uptake inhibitor. The 5-HT re-uptake system in the pineal probably differes from that in brain tissue. TADs had a marked effect on the metabolism of ³H-5HT in the rat pineal, in an organ culture system, MEL and N-acetylserotonin synthesis increased for the first 11 days and thereafter a slight decrease was observed. HTOH and HIAA also showed an initial increase followed by a slight decrease in synthesis. The synthesis of MTOH and MIAA was decreased. The possibility that TADs could affect HIOMT and SNAT synthesis and thereby change the metabolic pattern of 5-HT was investigated. TADs appeared to stimulate SNAT initially and thereafter a slight decrease from peak activity was observed. This is probably due to stimulation followed by development of subsensitivity of β-receptors, HIOMT activity also appeared to be affected by TADs. The existence of two types of HIOMT is suggested. There is a possibility that these changes in the metabolism of 5-HT could be implicated in the mechanism of action of TADs. , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 1983
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