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1.
Indian J Surg ; 75(1): 34-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24426381

RESUMO

Castleman's disease (CD) is a relatively rare and benign disorder. Pancreatic localization of CD is even more rare and is usually indistinguishable from pancreatic neoplasms. We report three cases of CD in which pancreas was all involved. One located in the tail of the pancreas, who accepted distal pancreatectomy, and the others in the head accepted enucleation. In addition, we review current data on its pathogenesis, imaging findings, diagnosis, differential diagnosis, and treatment.

2.
Int J Ayurveda Res ; 1(1): 30-6, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20532095

RESUMO

Migraine patients who do not respond to conventional therapy, develop unacceptable side-effects, or are reluctant to take medicines resort to complementary and alternative medicines (CAM). Globally, patients have been seeking various non-conventional modes of therapy for the management of their headaches. An Ayurvedic Treatment Protocol (AyTP) comprising five Ayurvedic medicines, namely Narikel Lavan, Sootshekhar Rasa, Sitopaladi Churna, Rason Vati and Godanti Mishran along with regulated diet and lifestyle modifications such as minimum 8 h sleep, 30-60 min morning or evening walk and abstention from smoking/drinking, was tried for migraine treatment. The duration of the therapy was 90 days. Out of 406 migraine patients who were offered this AyTP, 204 patients completed 90 days of treatment. Complete disappearance of headache and associated symptoms at completion of AyTP was observed in 72 (35.2%); mild episode of headache without need of any conventional medicines in 72 (35.2%); low intensity of pain along with conventional medicines in 50 (24.5%); no improvement in seven (3.4%) and worst pain was noted in three (1.4%) patients, respectively. In 144 (70.5%) of patients marked reduction of migraine frequency and pain intensity observed may be because of the AyTP. Though the uncontrolled open-label design of this study does not allow us to draw a definite conclusion, from this observational study we can make a preliminary assessment regarding the effectiveness of this ayurvedic treatment protocol.

3.
Genes Immun ; 8(8): 628-33, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17728790

RESUMO

Autoimmune diabetes shows extreme variation in age of onset and clinical presentation, although most studies have been done in children with the most severe subtype. Disease risk is strongly associated with HLA-DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2), but it has not been possible to separate the effects of the DR and DQ alleles. We have identified a large Bedouin kindred in which a high prevalence of islet autoimmunity is associated with two different DR3 haplotypes, one carrying the usual DQ2 and the other carrying DQA1*0102-DQB1*0502 (DQ5). Results of prospective follow-up studies indicate that DR3 is associated with the initial activation of islet autoimmunity whereas DQ2 is associated with early-onset and severe clinical disease. The association signals map to a 350-kb interval, thus implicating primary effects for DR3 and DQ2. Overall, our results emphasize the importance of prospective genetic studies that examine the full range of variation in the initiation, progression and expression of autoimmune disease.


Assuntos
Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Ilhotas Pancreáticas/imunologia , Adolescente , Adulto , Idade de Início , Idoso , Árabes/genética , Criança , Pré-Escolar , Feminino , Frequência do Gene , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Haplótipos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade
4.
J Clin Endocrinol Metab ; 84(1): 328-35, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9920103

RESUMO

Of 957 patients with type 1 diabetes without known Addison's disease 1.6% (n = 15) were positive for 21-hydroxylase autoantibodies. Among DQ8/DQ2 heterozygous patients, the percentage expressing 21-hydroxylase autoantibodies was 5% (10 of 208) vs. less than 0.5% of patients with neither DQ8 nor DQ2. Three of the diabetic patients found to have 21-hydroxylase autoantibodies on screening were subsequently diagnosed with Addison's disease. Overall, the genotype DQ8/DQ2, consisting of DRB1*0404/DQ8 with DRB1*0301/DQ2, was present in 14 of 21 patients with Addison's disease (8 of 12 with diabetes and 6 of 9 without diabetes or antiislet autoantibodies) vs. 0.7% of the general population (109 of 15,547; P < 10(-6)) and 11% of patients with DM without Addison's disease (62 of 578; P < 10(-6)). Among patients with diabetes with DQ8, Addison's disease was strongly associated with the specific DRB1 subtype, DRB1*0404 (8 of 9 patients from 8 families, in contrast to only 109 of 408 DQ8 DM patients with diabetes without Addison's disease having DRB1*0404; P < 0.001). Among 21-hydroxylase autoantibody-positive DQ8 patients, 80% with DRB1*0404 (12 of 15) had Addison's disease, in contrast to 1 of 10 autoantibody-positive patients with DRB1*0401 or DRB1*0402 (P < 0.001). We conclude that patients with DRB1*0404 and 21-hydroxylase autoantibodies are at high risk for Addison's disease. Patients with DRB1*0401 and DRB1*0402 have more limited progression to Addison's disease despite the presence of 21-hydroxylase autoantibodies.


Assuntos
Doença de Addison/etiologia , Alelos , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Esteroide 21-Hidroxilase/imunologia , Doença de Addison/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Cadeias HLA-DRB1 , Humanos , Lactente , Pessoa de Meia-Idade , Risco
5.
Hum Hered ; 48(6): 343-5, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9813457

RESUMO

A novel microsatellite marker was found within 48.5 kb of the Fas gene. The observed heterozygosity in 160 healthy unrelated controls was 0.78. There was no evidence of linkage to type I diabetes mellitus in 120 diabetic children using the transmission disequilibrium test.


Assuntos
Diabetes Mellitus Tipo 1/genética , Grupo com Ancestrais do Continente Europeu/genética , Ligação Genética , Repetições de Microssatélites , Polimorfismo Genético , Receptor fas/genética , Sequência de Bases , Criança , Primers do DNA , Frequência do Gene , Heterozigoto , Humanos
6.
Biochem Pharmacol ; 51(12): 1679-85, 1996 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-8687483

RESUMO

Glucuronide conjugates of arylamines are thought to be important in the carcinogenic process. This study investigated the pH stability and synthesis of glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites by human and dog liver. Both dog and human liver slices incubated with 0.06 mM [3H]-4-aminobiphenyl produced the N-glucuronide of 4-aminobiphenyl as the major product. After 2 hr of incubation, the N-glucuronide of 4-aminobiphenyl represented 52 and 27% of the total radioactivity recovered by HPLC in dog and human, respectively. When 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, or N-hydroxy-N-acetyl-4-aminobiphenyl was added to human microsomes containing [14C]UDP-glucuronic acid, a new product peak was detected by HPLC. At 0.5 mM, the rate of glucuronidation was N-hydroxy-N-acetyl-4-aminobiphenyl > N-hydroxy-4-aminobiphenyl > 4-aminobiphenyl. The rate of formation of the N-glucuronide of 4-aminobiphenyl was similar to that observed with benzidine and N-acetylbenzidine. The glucuronides of 4-aminobiphenyl and N-hydroxy-4-aminobiphenyl were both acid labile with T1/2 values of 10.5 and 32 min, respectively, at pH 5.5. The glucuronide of N-hydroxy-N-acetyl-4-aminobiphenyl was not acid labile with T1/2 values at pH 5.5 and 7.4 of 55 and 68 min, respectively. The glucuronide of 4-aminobiphenyl was the most acid labile conjugate examined. Thus, the glucuronide of 4-aminobiphenyl is a major product of dog and human liver slice metabolism and likely to play an important role in the carcinogenic process.


Assuntos
Compostos de Aminobifenil/metabolismo , Carcinógenos/metabolismo , Glucuronatos/metabolismo , Fígado/metabolismo , Compostos de Aminobifenil/química , Animais , Carcinógenos/química , Cromatografia Líquida de Alta Pressão , Cães , Glucuronatos/química , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares
7.
Carcinogenesis ; 16(12): 3069-74, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8603487

RESUMO

Glucuronidation of N-hydroxy arylamines is thought to be a necessary step in their initiation of bladder cancer. This was evaluated for the N-hydroxy metabolites of N-acetylbenzidine (ABZ). N'-Hydroxy-N-acetylbenzidine (N'-HA), N-hydroxy-N-acetylbenzidine (N-HA) and N-hydroxy- N,N'-diacetylbenzidine (N-HDA) were synthesized. Except for N'-HA, these compounds were quite stable. Ascorbic acid and/or acidic pH increased the stability of N'-HA. When each N-hydroxy compound was added to reaction mixtures containing [14C]UDP-glucuronic acid, 3 mM ascorbic acid and human liver microsomes a new product was detected by HPLC. Emulgen 911 was a better detergent than Triton X-100 for expressing microsomal activity, with maximal glucuronidation observed with 0.3% Emulgen 911. At 0.125 mM amine the rate of glucuronidation was N-HDA >> N'-HA = benzidine > ABZ > N-HA. In contrast, at 0.5 mM amine the rate of glucuronidation of N-HA was only exceeded by N-HDA. At pH 5.5 and 37 degrees C the t1/2 for the enzymatically prepared glucuronide conjugates of ABZ, N'-HA and N-HA were 7.5 min and 3.5 and 1.8 h respectively. For N-HDA > 90% of this glucuronide remained after 24 h. At pH 7.4 and 37 degrees C the t1/2 for the glucuronide conjugates of ABZ and N-HA were 2.3 and 2 h respectively, with the amounts remaining after 24 h for N'-HA and N-HDA being 75 and 90% respectively. At pH 6.5 the t1/2 for N'-HA was 14 h. Thus only glucuronides of ABZ and N'-HA exhibit pH-dependent changes in t1/2. Compared with ABZ, glucuronides the N-hydroxy metabolites are more stable at acidic pH. Acidic urine would be more likely to hydrolyze the glucuronide conjugate of ABZ than those of its N-hydroxy metabolites. Because these results are different from that hypothesized for arylmonoamines, a new model was developed to explain the role of N-oxidation, N-glucuronidation and N-acetylation in the carcinogenesis of benzidine, an aryldiamine.


Assuntos
Benzidinas/metabolismo , Carcinógenos/metabolismo , Glucuronatos/metabolismo , Acetilação , Benzidinas/química , Carcinógenos/química , Humanos , Concentração de Íons de Hidrogênio , Hidroxilação , Microssomos Hepáticos/metabolismo , Neoplasias da Bexiga Urinária/induzido quimicamente
8.
Diabetes ; 44(11): 1340-4, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7589834

RESUMO

As part of a general program of screening islet expression libraries we have identified a clone from a lambda gt11 human islet expression library that reacts with human diabetic sera and, upon sequencing, was determined to be the neuroendocrine islet autoantigen ICA512 (islet cell antigen 512). In the current communication, we describe the development of a radioassay for autoantibodies to ICA512 (ICA512AA) using in vitro transcribed and translated protein for production of labeled antigen. Our initial results indicate that this radioassay is significantly more sensitive than the enzyme-linked immunosorbant assay, which uses a COOH-terminal fragment of ICA512. The ICA512AA radioassay uses a 96-well format with membrane separation of antibody bound from free antigen and should be readily adaptable to automated large-scale screening. Only 7 microliters of serum is required for triplicate determinations. In order to determine the specificity and sensitivity of this assay and estimate its positive predictive value, we have studied 42 new-onset diabetic patients, 33 first-degree relatives of diabetic patients followed to diabetes, 694 islet cell antibody-negative (ICA-) relatives, and 205 normal control subjects. Thirty-eight percent of new-onset patients and 48% of relatives followed to diabetes express autoantibodies to ICA512 exceeding the 99th percentile of the normal control subjects. In contrast, only 1.4% of ICA- first-degree relatives were positive for ICA512 autoantibodies.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/imunologia , Proteínas de Membrana/imunologia , Estado Pré-Diabético/imunologia , Proteínas Tirosina Fosfatases/imunologia , Animais , Autoantígenos , Sequência de Bases , Clonagem Molecular , Primers do DNA , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Ensaio de Imunoadsorção Enzimática , Família , Seguimentos , Glutamato Descarboxilase/imunologia , Humanos , Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Proteínas de Membrana/biossíntese , Metionina/metabolismo , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Estado Pré-Diabético/sangue , Estado Pré-Diabético/genética , Valor Preditivo dos Testes , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/biossíntese , Coelhos , Técnica de Diluição de Radioisótopos , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores , Proteínas Recombinantes/análise , Proteínas Recombinantes/biossíntese , Valores de Referência , Reticulócitos/metabolismo , Sensibilidade e Especificidade , Radioisótopos de Enxofre , Fatores de Tempo
9.
Pharm Res ; 11(12): 1755-60, 1994 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7899240

RESUMO

Physicochemical effects caused by intestinal fluids on drugs in the gastrointestinal (GI) tract can be a contributing factor in food induced changes in bioavailability. To identify physicochemical properties of gemfibrozil that may be altered by endogenous and dietary lipids, in vitro studies were conducted in model systems approximating the conditions of the upper GI tract. Factors examined include pH, solubility in bile salt micellar and mixed micellar systems with monoolein and lecithin, effect of fatty acids, dissolution, wetting, and partitioning in triglyceride dispersions. Gemfibrozil was solubilized by glycocholate solutions in a manner typical of other lipids and a three-fold increase in solubility was observed over physiologic concentrations. Addition of increasing amounts of swelling amphiphiles (monoolein, lecithin) to glycocholate solutions resulted in a linear increase in solubility. Fatty acid salts had no effect on gemfibrozil solubilization by micellar solutions. The dissolution rate of gemfibrozil increased slightly in the presence of glycocholate relative to buffer, however, addition of monoolein increased the dissolution rate three-fold. In triglyceride dispersions of mixtures of lipids, monoolein increased the fraction of drug in the micellar subphase, whereas fatty acid reduced it. The results indicate that in the conditions of the fed state gemfibrozil solubility and dissolution could be substantially increased relative to the conditions in the fasted state.


Assuntos
Ácidos e Sais Biliares/farmacologia , Gorduras na Dieta/farmacologia , Genfibrozila/química , Lipídeos/farmacologia , Concentração de Íons de Hidrogênio , Solubilidade
10.
Drug Metab Dispos ; 22(6): 922-7, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7895611

RESUMO

N-Glucuronidation is an important pathway in aromatic amine metabolism. This study assessed N-glucuronidation of N-acetylbenzidine by human liver slices and microsomes. With slices, considerable metabolism of [3H]N-acetylbenzidine (0.2 mM) was observed during a 2-hr incubation. N-Acetylbenzidine N'-glucuronide represented significant metabolism in four different human liver samples (6-33% of the total recovered radioactivity following HPLC). Benzidine (11-43%), benzidine N-glucuronide (8-11%), and N,N'-diacetylbenzidine (0-2%) were also formed. The kinetics of N-acetylbenzidine N'-glucuronide formation were investigated using Triton X-100-pretreated microsomes. Data were best described by a two-component Michaelis-Menten model composed of both high-affinity (low KM) and low-affinity (high KM) UDP-glucuronsyltranosferases. The high- and low-affinity KMs were 0.36 +/- 0.02 and 1.07 +/- 0.12 mM, respectively. To help identify the UDP-glucuronosyltransferases metabolizing N-acetylbenzidine, 23 transferase substrates were tested for their ability to inhibit glucuronidation. At 0.25 mM, bilirubin, estriol, and 17-epiestriol were good inhibitors (< 50% of control). Dose-response inhibition studies with estriol and 4-aminobiphenyl demonstrated that each agent reached a plateau as its concentration was increased. IC50 for estriol and 4-aminobiphenyl was 0.15 +/- 0.03 and 0.57 +/- 0.06 mM, respectively. Complimentary inhibition was observed when these agents were combined at maximal inhibitory concentrations. These results suggest that more than one UDP-glucuronosyltransferase metabolizes N-acetylbenzidine. N-Glucuronidation represents a major pathway for N-acetylbenzidine metabolism in humans.


Assuntos
Benzidinas/metabolismo , Glucuronatos/metabolismo , Fígado/metabolismo , Idoso , Feminino , Glucuronosiltransferase/fisiologia , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade
11.
Carcinogenesis ; 15(9): 2003-7, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7923596

RESUMO

Although glucuronidation is considered an important pathway in aromatic amine-induced bladder cancer, benzidine glucuronidation has not been assessed in humans. Glucuronidation of benzidine was assessed with human liver microsomes and slices. Emulgen 911-treated microsomes exhibited a Km for benzidine of 0.8 +/- 0.06 mM and a Vmax of 4.2 +/- 0.7 nmol/mg protein/min. A variety of agents were tested for their ability to inhibit benzidine N-glucuronide formation. At 0.25 mM, estriol, 17-epiestriol, bilirubin, hyodeoxycholic acid and cyproheptadine were good inhibitors (< 50% of control). Dose-dependent inhibition studies with estriol, testosterone and 4-aminobiphenyl demonstrated that each agent reached a plateau as its concentration was increased. When these agents were combined at maximal inhibitory concentrations, additive inhibition was observed. These results suggest that more than one UDP-glucuronosyltransferase metabolizes benzidine. The cDNA clones pUDPGTh-1 and -2 encode transferases which metabolize hyodeoxycholic acid and estrogen derivatives, but neither transferase catalyzed benzidine glucuronidation. Slices were used to assess metabolism by intact tissue and converted [3H]benzidine (0.09 mM) to N-acetyl-benzidine. N-Glucuronides of both benzidine and N-acetylbenzidine were observed and represented 14-37% of the total recovered radioactivity. The amount of N-acetylbenzidine N'-glucuronide observed was proportional to the amount of N-acetylbenzidine produced. Thus, N-glucuronidation appears to represent a major pathway for metabolism of benzidine in humans. The extent of N-acetylation affects the proportion of benzidine and N-acetylbenzidine glucuronidated by human liver slices.


Assuntos
Benzidinas/metabolismo , Glucuronatos/metabolismo , Fígado/metabolismo , Idoso , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/metabolismo , Humanos , Cinética , Fígado/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Especificidade da Espécie , Trítio
12.
Pharmacol Biochem Behav ; 47(4): 779-88, 1994 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8029245

RESUMO

The purpose of this investigation was to determine the effect of physostigmine (Phy) and/or concurrent exercise on lactate, pyruvate, and L/P ratio in plasma, skeletal muscle, and brain tissue in male Sprague-Dawley rats. The Phy-dosed (Phy-D) and Phy-dosed + concurrent acute exercise (Phy-D + CAE) groups elicited significantly higher L/P ratios in plasma compared to the acutely exercised (AE) group at 30 min postexercise. Physostigmine dosing, with or without exercise, resulted in significantly lower muscle pyruvate levels, from 30 to 50 min postdrug administration, in Phy-D and Phy-D + CAE groups compared to the AE group. In the brain, lactate values were significantly elevated in the acutely exercised groups at 5 min postexercise with or without Phy dosing. However, at 15 to 30 min postexercise, lactate values were significantly elevated in the Phy-D + CAE compared to the AE group. These data suggest that when Phy is administered prior to a 20-min moderately intensive exercise bout, there is an accumulation of lactate for a prolonged period of time in recovery.


Assuntos
Lactatos/metabolismo , Esforço Físico/fisiologia , Fisostigmina/farmacologia , Piruvatos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cinética , Lactatos/sangue , Ácido Láctico , Masculino , Músculos/efeitos dos fármacos , Músculos/metabolismo , Piruvatos/sangue , Ácido Pirúvico , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
13.
Pharmacol Biochem Behav ; 46(4): 827-34, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8309962

RESUMO

This study reports the modulatory effects of physostigmine (Phy) and concurrent acute exercise on the time course of cholinesterase (ChE) activity, the rate of decarbamylation (Kd), and half-time of recovery of ChE in red blood cells (RBC) and various tissues of rats. Acute exercise equivalent to 80% VO2-max (maximal oxygen consumption) transiently increased the RBC ChE activity, whereas Phy decreased ChE activity in RBC and various tissues. Physostigmine along with concurrent acute exercise increased the Kd in RBC, brain, and heart by 56.4%, 66.7%, and 139%, respectively, compared to Phy alone. The Kd in diaphragm and muscle decreased to 14.1% and 56.2%, respectively, compared to Phy alone. The variation in Kd might be due to the effect of concurrent acute exercise on the redistribution of Phy in various tissues of rat as a result of changes in blood flow.


Assuntos
Colinesterases/sangue , Esforço Físico/fisiologia , Fisostigmina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Masculino , Músculos/efeitos dos fármacos , Músculos/enzimologia , Miocárdio/enzimologia , Consumo de Oxigênio/efeitos dos fármacos , Fisostigmina/farmacocinética , Ratos , Ratos Sprague-Dawley , Músculos Respiratórios/efeitos dos fármacos , Músculos Respiratórios/enzimologia
14.
Carcinogenesis ; 14(12): 2605-11, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8269633

RESUMO

While N-glucuronidation is an important pathway for metabolism of aromatic amines, it has not been demonstrated for N-acetylbenzidine. A glucuronide of N-acetylbenzidine was synthesized and identified by mass spectrometry as N-acetylbenzidine-N'-glucuronide. This N'-glucuronide is acid labile with a t1/2 of 4 min at pH 5.3. A similar acid lability was also observed with benzidine-N-glucuronide. The formation of N-acetylbenzidine-N'-glucuronide was assessed with liver slices and microsomes prepared from human, dog and rat. When 0.014 mM [3H]N-acetylbenzidine was incubated with human liver slices a significant amount of N-acetylbendizine-N'-glucuronide was produced (8-26% of the total radioactivity recovered). With higher concentrations of [3H]N-acetylbenzidine (1 mM) rat slices also produced N-acetylbenzidine-N'-glucuronide. However, N'-glucuronide formation was not detected with dog liver slices incubated with either 0.014 or 1 mM [3H]N-acetylbenzidine. N-Acetylbenzidine-N'-glucuronide formation was observed with microsomes prepared from human, dog and rat. To assess maximum activity four detergents were used at two concentrations. With or without detergent activation the relative amount of glucuronidation was human > > dog > rat. The rate of benzidine N-glucuronide formation was 4.3- and 1.6-fold greater than N-acetylbenzidine-N'-glucuronide in dog and rat respectively, while in human both rates were similar (1.1-fold). With or without detergent activation the relative amount of benzidine-N-glucuronide formation was human > dog > > rat. N-Glucuronidation of [3H]N,N'-diacetylbenzidine was not observed. Thus N-actylbenzidine-N'-glucuronide formation appears to be an important pathway for metabolism of N-acetylbenzidine, especially in humans. Due to their acid lability, formation of the N-glucuronides of N-acetylbenzidine and benzidine provides a mechanism for hepatic detoxification and accumulation of these carcinogens in the bladder. A new model is described illustrating the effect of N-glucuronidation and the influence of N-acetylation on arylmono- and aryldiamine-induced bladder carcinogenesis.


Assuntos
Benzidinas/metabolismo , Glucuronatos/metabolismo , Fígado/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Cães , Glucuronosiltransferase/metabolismo , Humanos , Técnicas In Vitro , Espectrometria de Massas , Microssomos Hepáticos/enzimologia , Ratos , Especificidade da Espécie
15.
Pharmacol Biochem Behav ; 45(3): 713-7, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8332628

RESUMO

The interaction of physostigmine (Phy) and exercise on choline-acetyltransferase (ChAT) and acetylcholinesterase (AChE) have been studied in the fast extensor digitorum longus (EDL) and slow soleus muscles of rat. ChAT decreased significantly by trained exercise in EDL muscle and Phy prolonged this effect even up to 24 h. Soleus muscles showed a small increase of ChAT due to exercise but Phy + exercise did not change significantly. Both EDL and soleus showed a marked decrease in AChE activity due to subacute administration of Phy + trained exercise, exhibiting an additive effect. No recovery was observed in ChAT and AChE activities of EDL even after 24 h in Phy + trained exercise group. Our results suggest that Phy and exercise has significant effect on the synthetic (ChAT) and degradative (AChE) enzymes of acetylcholine in active EDL muscle. Exercise has prolonged the inhibitory effect of Phy on ChAT and AChE activities both in active EDL and passive soleus muscles. This study showed that Phy + exercise modified the functional activity of cholinergic system in EDL and soleus muscles.


Assuntos
Acetilcolinesterase/metabolismo , Colina O-Acetiltransferase/metabolismo , Músculos/enzimologia , Condicionamento Físico Animal , Animais , Masculino , Músculos/efeitos dos fármacos , Fisostigmina/farmacologia , Ratos , Ratos Sprague-Dawley
16.
Carcinogenesis ; 14(5): 893-7, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8389254

RESUMO

Dog is an animal model for assessing aromatic amine-induced bladder cancer, and hepatic N-glucuronidation is proposed as an important pathway leading to initiation of carcinogenesis. Therefore, benzidine N-glucuronidation was evaluated with dog liver microsomes and slices. Microsomal benzidine UDP-glucuronosyltransferase activity was increased with a variety of detergents. For kinetic analysis, native microsomal preparations were separated into treated (detergent treated, not centrifuged) or soluble (detergent treated, centrifuged) fractions. The detergents Triton X-100, Lubrol PX, Emulgen 911 and CHAPS increased the specific activity of treated fractions relative to the native microsomes 3- to 6-fold. The specific activities of the soluble fractions were highest with Emulgen 911 and CHAPS at a detergent-to-protein ratio of 1. Subsequent studies used Emulgen 911 or CHAPS. Similar results were observed with either preparation. For treated preparations, the Km and Vmax values were 0.142 +/- 0.006 mM and 0.65 +/- 0.1 nmol/mg protein/min respectively. A variety of chemicals were tested for their effect on benzidine N-glucuronide formation. At 0.1 mM, the only effective inhibitors (< 50% of control) were 2-aminofluorene, estriol, 17-epiestriol, 2-OH-estrone, and 4-OH-estrone. With Emulgen-treated microsomes, the Ki values for 2-aminofluorene, 4-aminobiphenyl and estriol were 0.114 +/- 0.014, 0.347 +/- 0.032 and 0.047 +/- 0.003 mM respectively. 2-Aminofluorene and estriol were non-competitive inhibitors, while 4-aminobiphenyl was a competitive inhibitor. Slices incubated with these chemicals exhibited an inhibition profile similar to that observed with microsomes. Thus, N-glucuronidation of benzidine may be an important metabolic pathway in dog. Inhibition of benzidine N-glucuronidation by estriol and catechol estrones may be important in vivo events in aromatic amine-induced carcinogenesis.


Assuntos
Benzidinas/metabolismo , Glucuronatos/metabolismo , Fígado/metabolismo , Microssomos Hepáticos/enzimologia , Compostos de Aminobifenil/farmacologia , Animais , Detergentes/farmacologia , Cães , Estriol/farmacologia , Fluorenos/farmacologia , Técnicas In Vitro , Cinética , Nonoxinol/farmacologia , Testosterona/farmacologia
17.
Xenobiotica ; 23(2): 193-203, 1993 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8498082

RESUMO

1. Oxidative metabolism of the bladder carcinogens FANFT/ANFT was examined in vitro in guinea pig (resistant species) relative to rat (susceptible species). 2. The total rate of ANFT hepatic metabolism by guinea pig (soluble metabolites plus protein bound, 354 pmol/min per mg protein) was approx. 4 times that in rat. 3. The total rate of FANFT metabolism was similar in both species and approx. one-quarter that for ANFT in guinea pig. In rat, the rate of total metabolism of FANFT and ANFT was similar. 4. Cytochrome P450 inhibitors, 2,4-dichloro-6-phenylphenoxyethylamine, 7,8-benzoflavone, and n-octylamine largely inhibited metabolism in guinea pig, but had little effect in rat. 5. H.p.l.c. analysis of ANFT metabolites indicated distinctly different products in guinea pig compared to rat. 7,8-Benzoflavone decreased metabolite formation by 80% in guinea pig, but only 30% in rat. 6. Flavin-dependent monooxygenases may participate in metabolism of these carcinogens in rat, but not guinea pig. 7. Because ANFT is thought to be a more proximate carcinogen than FANFT, the increased rate of ANFT metabolism and the formation of different products in guinea pig compared to rat may partially explain the resistance of guinea pig to FANFT-induced bladder cancer.


Assuntos
Carcinógenos/metabolismo , FANFT/análogos & derivados , FANFT/metabolismo , Fígado/metabolismo , NADP/metabolismo , Animais , DNA/metabolismo , Inibidores Enzimáticos/farmacologia , Cobaias , Rim/metabolismo , Fígado/enzimologia , Masculino , Microssomos Hepáticos/enzimologia , Especificidade de Órgãos , Oxirredução , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Neoplasias da Bexiga Urinária/induzido quimicamente
18.
Carcinogenesis ; 13(7): 1235-40, 1992 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1638692

RESUMO

The mechanism by which benzidine induces bladder cancer in dog was evaluated by assessing metabolism of [3H]benzidine by dog liver slices and microsomes. Slices incubated with 0.05 mM [3H]benzidine exhibited a 32.5 min incubated with 0.05 mM [3H]benzidine exhibited a 32.5 min peak, which was also produced when microsomal incubations were supplemented with UDP-glucuronic acid. In contrast to microsomes, very little of the 32.5 min peak was produced with the 100,000 g supernatant fraction. Microsomal metabolism was increased 5-fold by pretreatment with Triton X-100. Very little activity was observed with rat microsomes in either the presence or absence of Triton X-100. This metabolite was also generated by incubating benzidine with glucuronic acid at 4 degrees C for 3 days. Thermospray MS identified this metabolite as benzidine N-glucuronide. At 37 degrees C, the t1/2 stability of purified N-glucuronide was 99, 25 and 3 min in dog urine adjusted to pH 7.3, 6.3 and 5.3 respectively. The N-glucuronide was quite stable at pH 9.3, in dog plasma, and in aprotic solvents for 4 h at 37 degrees C. Relative to benzidine, its N-glucuronide is weakly bound to plasma proteins but not more reactive with DNA. Thus, detoxification by liver provides a mechanism for accumulation of benzidine in acidic urine, uptake of benzidine into bladder epithelium, and activation of benzidine in bladder. The liver and N-glucuronidation play a potentially important role in the species specificity of benzidine carcinogenesis.


Assuntos
Benzidinas/metabolismo , Benzidinas/toxicidade , DNA/metabolismo , Glucuronatos/metabolismo , Glucuronosiltransferase/metabolismo , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Uridina Difosfato Ácido Glucurônico/metabolismo , Neoplasias da Bexiga Urinária/induzido quimicamente , Animais , Benzidinas/síntese química , Benzidinas/isolamento & purificação , Cães , Glucuronatos/síntese química , Glucuronatos/isolamento & purificação , Técnicas In Vitro , Espectrometria de Massas , Neoplasias da Bexiga Urinária/metabolismo
19.
Pharmacol Biochem Behav ; 42(1): 67-73, 1992 May.
Artigo em Inglês | MEDLINE | ID: mdl-1528949

RESUMO

Physostigmine (Phy) is metabolized to eseroline, a phenolic compound that appears to alter mitochondrial functions. The effect of Phy on recovery from exercise and on time course of plasma lactate and pyruvate levels following an acute bout of exercise (AE) was examined in untrained and trained (ET) rats. Phy alone elicited significantly higher plasma lactate and pyruvate levels than sedentary control. AE + Phy had a significantly higher plasma lactate and pyruvate levels compared to AE 2 min postadministration. From 5-30 min postexercise, lactate and pyruvate levels did not differ between these two acutely exercised groups. ET + Phy exhibited significantly lower levels of plasma lactate and pyruvate from 5-60 min postexercise compared to ET. The data show that the "additive" effect of Phy on postexercise plasma lactate and pyruvate levels can be attenuated by an enhanced fitness level in these rats.


Assuntos
Lactatos/sangue , Condicionamento Físico Animal , Fisostigmina/farmacologia , Piruvatos/sangue , Animais , Ácido Láctico , Masculino , Esforço Físico , Ácido Pirúvico , Ratos , Ratos Endogâmicos
20.
Pharmacol Biochem Behav ; 39(2): 337-43, 1991 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-1946575

RESUMO

This study sought to determine whether the choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) enzymes in the brain were affected in a regionally selective manner by chemical and physical stressors: 1) subacute administration of physostigmine (Phy); 2) exercise; and 3) the combination of these two stressors. ChAT and AChE activities in corpus striatum were significantly decreased due to Phy as well as Phy + exercise. This suggests that corpus striatum is affected by chemical stressors but more so by the combination of chemical and physical stressors. The brainstem is the only region which showed inhibition of ChAT activity due to exercise. Subacute Phy also inhibited brainstem ChAT activity. The hippocampus showed significant decrease in ChAT activity due to Phy + exercise but not due to Phy alone. These results suggest that the brain regions involved with control of motor, autonomic and cognitive functions were affected by subacute Phy and exercise. These data are consistent with the hypothesis that the responsiveness of these brain regions to different stressors is a function of the level of ongoing cholinergic activity and that elevations in ACh levels due to AChE inhibition may have long-term effects on the regulation of ChAT and AChE activities through a negative feedback mechanism.


Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/enzimologia , Colina O-Acetiltransferase/metabolismo , Inibidores da Colinesterase/farmacologia , Condicionamento Físico Animal , Animais , Encéfalo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/enzimologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Fisostigmina/farmacologia , Ratos , Ratos Endogâmicos
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