RESUMO
BACKGROUND: Exposure to childhood maltreatment (CM) increases the risk of psychiatric morbidity in youths. The new Complex Post-Traumatic Stress Disorder (CPTSD) diagnosis captures the heterogeneity and complexity of clinical outcomes observed in youths exposed to CM. This study explores CPTSD symptomatology and its association with clinical outcomes, considering the impact of CM subtypes and age of exposure. METHODS: Exposure to CM and clinical outcomes were evaluated in 187 youths aged 7-17 (116 with psychiatric disorder; 71 healthy controls) following the Tools for Assessing the Severity of Situations in which Children are Vulnerable (TASSCV) structured interview criteria. CPTSD symptomatology was explored by confirmatory factor analysis, considering four subdomains: post-traumatic stress symptoms, emotion dysregulation, negative self-concept and interpersonal problems. RESULTS: Youths exposed to CM (with or without psychiatric disorders) showed greater internalizing, externalizing and other symptomatology, worse premorbid adjustment and poorer overall functioning. Youth with psychiatric disorder and exposed to CM reported more CPTSD symptomatology, psychiatric comorbidity and polypharmacy and earlier onset of cannabis use. Different subtypes of CM and the developmental stage of exposure differentially impact CPTSD subdomains. LIMITATIONS: Small percentage of resilient youths was studied. It was not possible to explore specific interactions between diagnostic categories and CM. Direct inference cannot be assumed. CONCLUSIONS: Gathering information on type and age of exposure to CM is clinically useful to understand the complexity of psychiatric symptoms observed in youths. Inclusion of the CPTSD diagnosis should increase the implementation of early specific interventions, improving youths' functioning and reducing the severity of clinical outcomes.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Criança , Humanos , Adolescente , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Classificação Internacional de Doenças , Comorbidade , AutoimagemRESUMO
Malaria caused by Plasmodium affects millions people worldwide. Plasmodium consumes hemoglobin during its intraerythrocytic stage leaving toxic heme. Parasite detoxifies free heme through formation of hemozoin (ß-hematin) pigment. Proteolysis of hemoglobin and formation of hemozoin are two main targets for antimalarial drugs. Quinoline antimarial drugs and analogs (ß-carbolines or nitroindazoles) were studied as inhibitors of ß-hematin formation. The most potent inhibitors were quinacrine, chloroquine, and amodiaquine followed by quinidine, mefloquine and quinine whereas 8-hydroxyquinoline and ß-carbolines had no effect. Compounds that inhibited ß-hematin increased free hemin that promoted peroxidative reactions as determined with TMB and ABTS substrates. Hemin-catalyzed peroxidative reactions were potentiated in presence of proteins (i.e. globin or BSA) while antioxidants and peroxidase inhibitors decreased peroxidation. Free hemin increased by chloroquine action promoted oxidative reactions resulting in inhibition of proteolysis by three cysteine proteases: papain, ficin and cathepsin B. Glutathione reversed inhibition of proteolysis. These results show that active quinolines inhibit hemozoin and increase free hemin which in presence of H2O2 that abounds in parasite digestive vacuole catalyzes peroxidative reactions and inhibition of cysteine proteases. This work suggests a link between the action of quinoline drugs with biochemical processes of peroxidation and inhibition of proteolysis.
Assuntos
Antimaláricos/farmacologia , Cisteína Proteases/metabolismo , Hemeproteínas/antagonistas & inibidores , Hemina/metabolismo , Plasmodium/efeitos dos fármacos , Quinolinas/farmacologia , Oxirredução , ProteóliseRESUMO
Norharman and harman are naturally occurring beta-carboline alkaloids exhibiting a wide range of biological, psychopharmacological, and toxicological actions. They occur in foods and tobacco smoke and also appear endogenously in humans. In this research, metabolic and kinetic studies with cytochrome P450 enzymes and human liver microsomes showed that beta-carbolines were efficiently oxidized to several ring-hydroxylated and N-oxidation products that were subsequently identified and quantified. 6-Hydroxy- beta-carboline (6-hydroxynorharman and 6-hydroxyharman) was a major metabolite efficiently produced (high kcat and low Km) by P450 1A2 and 1A1 and to a minor extent by P450 2D6, 2C19 and 2E1. 3-Hydroxy-beta-carboline (3-hydroxynorharman and 3-hydroxyharman), another major metabolite, was specifically produced by P450 1A2 and 1A1, whereas beta-carboline-N(2)-oxide (harman-2-oxide and norharman-2-oxide) was produced by P450 2E1. The same pattern of metabolism was confirmed for human liver microsomes. Oxidative metabolism for harman was slightly higher than norharman, but norharman showed lower Km values. The oxidation of beta-carbolines is a detoxication route performed mainly by P450 1A2 and 1A1, with the participation of P450 2D6, 2C19, and 2E1, as additional contributors. Then, individual variations in the levels and activity of these P450s may influence biotransformation of beta-carboline alkaloids and their ultimate biological effects. beta-Carbolines were previously reported as comutagens and/or inhibitors of mutagens activated by P450 1A enzymes such as heterocyclic amines and polycyclic hydrocarbons. Results in this work show that beta-carbolines are good ligands and substrates for P450 1A2/1A1, contributing to the explanation of some of their toxicological effects.
Assuntos
Sistema Enzimático do Citocromo P-450/fisiologia , Harmina/análogos & derivados , Carbolinas , Citocromo P-450 CYP1A1/fisiologia , Citocromo P-450 CYP1A2/fisiologia , Harmina/metabolismo , Humanos , Hidroxilação , Microssomos Hepáticos/metabolismo , OxirreduçãoRESUMO
Monoamine oxidase (MAO) catalyzes the oxidative deamination of amines and neurotransmitters and is involved in mood disorders, depression, oxidative stress, and adverse pharmacological reactions. This work studies the inhibition of human MAO-A by Hypericum perforatum, Peganum harmala, and Lepidium meyenii, which are reported to improve and affect mood and mental conditions. Subsequently, the antioxidant activity associated with the inhibition of MAO is determined in plant extracts for the first time. H. perforatum inhibited human MAO-A, and extracts from flowers gave the highest inhibition (IC50 of 63.6 µg/mL). Plant extracts were analyzed by HPLC-DAD-MS and contained pseudohypericin, hypericin, hyperforin, adhyperforin, hyperfirin, and flavonoids. Hyperforin did not inhibit human MAO-A and hypericin was a poor inhibitor of this isoenzyme. Quercetin and flavonoids significantly contributed to MAO-A inhibition. P. harmala seed extracts highly inhibited MAO-A (IC50 of 49.9 µg/L), being a thousand times more potent than H. perforatum extracts owing to its content of ß-carboline alkaloids (harmaline and harmine). L. meyenii root (maca) extracts did not inhibit MAO-A. These plants may exert protective actions related to antioxidant effects. Results in this work show that P. harmala and H. perforatum extracts exhibit antioxidant activity associated with the inhibition of MAO (i.e., lower production of H2O2).
Assuntos
Antidepressivos/farmacologia , Antioxidantes/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Extratos Vegetais/farmacologia , Alcaloides/farmacologia , Antracenos , Flavonoides/farmacologia , Humanos , Hypericum/química , Lepidium/química , Peganum/química , Perileno/análogos & derivados , Perileno/farmacologia , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Terpenos/farmacologia , Triterpenos/farmacologiaRESUMO
Peganum harmala L. is a medicinal plant from the Mediterranean region and Asia currently used for recreative psychoactive purposes (Ayahuasca analogue), and increasingly involved in toxic cases. Its psychopharmacological and toxicological properties are attributed to quinazoline and ß-carboline alkaloids. In this work three major quinazoline alkaloids were isolated from P. harmala extracts and characterized as peganine (vasicine), deoxypeganine (deoxyvasicine) and a novel compound identified by HPLC-DAD-MS and NMR as peganine ß-d-glucopyranosyl-(1 â 6)-ß-d-glucopyranoside (peganine glycoside). Peganine appeared in flowers and leaves in high levels; high amounts of deoxypeganine and peganine were found in immature and green fruits whereas peganine and peganine glycoside accumulated in high amount in dry seeds reaching up to 1 and 3.9% (w/w), respectively. Roots and stems contained low amount of quinazolines. Seeds extracts containing both quinazoline and ß-carboline alkaloids potently inhibited human monoamine oxidase (MAO)-A. However, quinazoline alkaloids did not contribute to MAO inhibition that was due to ß-carbolines, suggesting that MAO-related psychoactive or toxic actions do not arise from quinazolines. Quinazoline alkaloids were poor radical scavengers in the ABTS assay whereas seed extracts had good activity. Quinazoline alkaloids are known to exert bronchodilator and abortifacient actions, and could contribute to such effects reported in P. harmala.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Peganum/química , Quinazolinas/química , Quinazolinas/farmacologia , Alcaloides/análise , Antioxidantes/química , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão , Dissacarídeos/análise , Dissacarídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Plantas Medicinais/química , Quinazolinas/análise , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
ß-glucans exhibited in cell walls of several pathogens as bacteria or fungi are sensed by pathogen recognition receptors such as scavenger receptors present in antigen presenting cells, i.e., macrophages. ß-glucans obtained from Shiitake mushrooms were chemically characterized. A ß-glucan supplemented diet was assayed for 30 days in rabbits aiming to characterize the immune response elicited in blood-derived macrophages. M1 and M2 profiles of macrophage differentiation were confirmed in rabbits by in vitro stimulation with IFN-γ and IL-4 and marker quantification of each differentiation pathway. Blood derived macrophages from rabbits administered in vivo with the ß-glucan supplemented diet showed higher IL-4, IFN-γ and RAGE together with lower IL-10 relative expression, indicative of an ongoing immune response. Differences in IL-1ß, IL-13 and IL-4 expression were also found in rabbit sera by ELISA suggesting further stimulation of the adaptive response. Recent challenges in the rabbit industry include the search of diet supplements able to elicit an immune stimulation with particular interest in facing pathogens such as viruses or bacteria. ß-glucans from fungi may contribute to maintain an immune steady state favouring protection and thus reducing antibiotic treatment.
RESUMO
Metabolic enzymes are involved in the activation/deactivation of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyiridine (MPTP) neurotoxin and its naturally occurring analogs 2-methyltetrahydro-ß-carbolines. The metabolic profile and biotransformation of these protoxins by three enzymes, monoamine oxidase (MAO), cytochrome P450, and heme peroxidases (myeloperoxidase and lactoperoxidase), were investigated and compared. The metabolite profile differed among the enzymes investigated. MAO and heme peroxidases activated these substances to toxic pyridinium and ß-carbolinium species. MAO catalyzed the oxidation of MPTP to 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP(+)), whereas heme peroxidases catalyzed the oxidation of MPDP(+) to 1-methyl-4-phenylpyridinium (MPP(+)) and of 2-methyltetrahydro-ß-carboline to 2-methyl-3,4-dihydro-ß-carbolinium cation (2-Me-3,4-DH ß C(+)). These substances were inactivated by cytochrome P450 2D6 through N-demethylation and aromatic hydroxylation (MPTP) and aromatic hydroxylation (2-methyltetrahydro-ß-carboline). In conclusion, the toxicological effects of these protoxins might result from a balance between the rate of their activation to toxic products (i.e., N-methylpyridinium-MPP(+) and MPDP(+)- and N-methyl--ß--carbolinium- ßC(+)-) by MAO and heme peroxidases and the rate of inactivation (i.e., N-demethylation, aromatic hydroxylation) by cytochrome P450 2D6.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Carbolinas/metabolismo , Enzimas/metabolismo , Metabolômica , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/química , Carbolinas/química , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Monoaminoxidase/metabolismo , Oxirredução , Peroxidases/metabolismo , Compostos de Piridínio/química , Compostos de Piridínio/metabolismoRESUMO
Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDPâº/MPPâº) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (ß-carboline), 9-methylnorharman (9-methyl-ß-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDPâº/MPPâº, in human mitochondria (IC50 of 0.18, 3.1, 9.9, 7.3, and 12.6 µM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC50 of 0.15 µM), a known neuroprotectant. The naturally-occurring ß-carbolines, harmine, harmaline and tetrahydro-ß-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5-nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC50 of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/antagonistas & inibidores , Antioxidantes/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Neurotoxinas/antagonistas & inibidores , Carbolinas/farmacologia , Cromatografia Líquida de Alta Pressão , Harmina/análogos & derivados , Harmina/farmacologia , Humanos , Indazóis/farmacologia , Espectrometria de Massas , Azul de Metileno/farmacologia , Mitocôndrias/metabolismo , Monoaminoxidase/efeitos adversos , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxirredução , Selegilina/farmacologiaRESUMO
Monoamine oxidase (MAO) B is a mitochondrial enzyme selectively involved in the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to toxic pyridinium cations producing Parkinsonism in animal models. Various synthesized 5-nitroindazoles, 6-nitroindazole and the neuroprotectant 7-nitroindazole were examined as inhibitors of MAO and as antioxidants and radical scavengers. The oxidation of MPTP by human MAO-B and mitochondria was assessed by HPLC. Simple nitroindazoles inhibited MPTP oxidation to 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) in a competitive and reversible manner. 5-Nitroindazole (IC(50)=0.99 microM, K(i)=0.102 microM) and 6-nitroindazole (IC(50)=2.5 microM) were better inhibitors of human MAO-B than 7-nitroindazole (IC(50)=27.8 microM). 6-Nitroindazole also inhibited MAO-A. Nitroindazole isomers were good hydroxyl radical (OH(*)) scavengers, with 5-nitro-, 6-nitro- and 7-nitroindazole showing similar activity (k approximately 10(10) M(-1) s(-1)). Neuroprotective actions of nitroindazoles (7-nitroindazole) could be linked to their MAO-inhibitory and antiradical properties besides inhibition on nitric oxide synthase (NOS). 5-Nitro- and 6-nitroindazole, previously reported as weak NOS inhibitors, were better inhibitors of human MAO-B and more active against MPTP neurotoxin oxidation (lower MPDP(+) and MPP(+) levels) than 7-nitroindazole and acted as good radical scavengers and could be potential neuroprotective agents in addition to MAO-B inhibitors.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/antagonistas & inibidores , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Indazóis/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Compostos de Piridínio/metabolismo , Sequestradores de Radicais Livres/farmacologia , Humanos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxirredução/efeitos dos fármacosRESUMO
Nitroreductases reduce nitroaromatic compounds and other oxidants in living organisms, having interesting implications in environmental and human health. A putative nitrobenzoate reductase encoding gene (lp_0050) was recently annotated in the completed DNA sequence of lactic acid bacterium Lactobacillus plantarum WCFS1 strain. In this research, this L. plantarum gene was cloned and expressed, and the corresponding protein (PnbA) was biochemically characterized. This L. plantarum PnbA reductase is a 216 amino acid residue FMN-flavoprotein, which exhibits 23% identity with Pseudomonas putida and Ralstonia eutropha nitroreductases and <11% identity with those from enterobacteria such as E. cloacae . This reductase also showed 32-43% identity (65-72% similarity) to predicted PnbA proteins from other lactic acid bacteria. It utilized a wide range of electron acceptors including dichlorophenolindophenol (DCPIP), nitroblue tetrazolium (NBT), ferricyanide, and quinones (menadione, benzoquinone), but not pyridinium cations (paraquat and N-methyl-beta-carbolines), and it was inhibited by dicoumarol and diphenyliodonium. HPLC-MS and spectroscopic data showed that it specifically catalyzed the reduction of the 4-nitroaromatic group to the corresponding hydroxylamine in the presence of NAD(P)H. Kinetics parameters (V(max) and K(m)) showed a higher efficiency for the reduction of 2,4-dinitrobenzoate than for the reduction of 4-nitrobenzoate. It was chemoselective for the reduction of 4-nitrobenzoates, being unable to reduce other nitroaromatics. Then, L. plantarum PnbA reductase might be more specific than other microbial nitroreductases that reduce a wider range of nitroaromatic compounds. The physiological and functional role of nitroreductases remain unknown; however, their presence in lactic acid bacteria widely occurring in foods and the human intestinal tract should be of further interest.
Assuntos
Proteínas de Bactérias/química , Ácido Láctico/metabolismo , Lactobacillus plantarum/enzimologia , Nitrorredutases/química , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Proteínas de Bactérias/metabolismo , Clonagem Molecular , Mononucleotídeo de Flavina/química , Mononucleotídeo de Flavina/metabolismo , Microbiologia de Alimentos , Humanos , Intestinos/microbiologia , Cinética , Lactobacillus plantarum/química , Lactobacillus plantarum/genética , Lactobacillus plantarum/isolamento & purificação , Dados de Sequência Molecular , Nitrobenzoatos/química , Nitrobenzoatos/metabolismo , Nitrorredutases/genética , Nitrorredutases/isolamento & purificação , Nitrorredutases/metabolismo , Oxirredução , Alinhamento de Sequência , Especificidade por SubstratoRESUMO
2-Methyl-1,2,3,4-tetrahydro-beta-carboline (2-Me-THbetaC) and 2,9-dimethyl-1,2,3,4-tetrahydro-beta-carboline (2,9-diMe-THbetaC) are naturally occurring analogs of the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), whereas their corresponding aromatic 2-methyl-beta-carbolinium cations resemble 1-methyl-4-phenylpyridinium (MPP(+)) and are considered potential toxins involved in Parkinson's disease (PD). To become toxicants, 2-methyltetrahydro-beta-carbolines need to be oxidized (aromatized) by human metabolic enzymes to pyridinium-like (beta-carbolinium) cations as occur with MPTP/MPP(+) model. In contrast to MPTP, human MAO-A or -B were not able to oxidize 2-Me-THbetaC to pyridinium-like cations. Neither, cytochrome P-450 2D6 or a mixture of six P450 enzymes carried out this oxidation in a significant manner. However, 2-Me-THbetaC and 2,9-diMe-THbetaC were efficiently oxidized by horseradish peroxidase (HRP), lactoperoxidase (LPO), and myeloperoxidase (MPO) to 2-methyl-3,4-dihydro-beta-carbolinium cations (2-Me-DHbetaC(+), 2,9-diMe-DHbetaC(+)) as the main products, and detectable amount of 2-methyl-beta-carbolinium cations (2-Me-betaC(+), 2,9-diMe-betaC(+)). The apparent kinetic parameters (k(cat), k(4)) were similar for HRP and LPO and higher for MPO. Peroxidase inhibitors (hydroxylamine, sodium azide, and ascorbic acid) highly reduced or abolished this oxidation. Although MPTP was not oxidized by peroxidases; its intermediate metabolite 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP(+)) was efficiently oxidized to MPP(+) by heme peroxidases. It is concluded that heme peroxidases could be key catalysts responsible for the aromatization (bioactivation) of endogenous and naturally occurring N-methyltetrahydro-beta-carbolines and related protoxins to toxic pyridinium-like cations resembling MPP(+), suggesting a role for these enzymes in toxicological and neurotoxicological processes.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/química , Carbolinas/química , Peroxidases/química , 1-Metil-4-fenilpiridínio/química , Cátions , Cromatografia Líquida de Alta Pressão/métodos , Heme/química , Cinética , Modelos Químicos , Neurotoxinas/química , Oxirredução , Compostos de Piridínio/química , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria UltravioletaRESUMO
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin is a chemical inducer of Parkinson's disease (PD) whereas N-methylated beta-carbolines and isoquinolines are naturally occurring analogues of MPTP involved in PD. This research has studied the oxidation of MPTP by human CYP2D6 (CYP2D6*1 and CYP2D6*10 allelic variants) as well as by a mixture of cytochrome P450s-resembling HLM, and the products generated compared with those afforded by human monoamine oxidase (MAO-B). MPTP was efficiently oxidized by CYP2D6 to two main products: MPTP-OH (p-hydroxylation) and PTP (N-demethylation), with turnover numbers of 10.09 min-1 and Km of 79.36+/-3 microM (formation of MPTP-OH) and 18.95 min-1 and Km 69.6+/-2.2 microM (PTP). Small amounts of dehydrogenated toxins MPDP+ and MPP+ were also detected. CYP2D6 competed with MAO-B for the oxidation of MPTP. MPTP oxidation by MAO-B to MPDP+ and MPP+ toxins (bioactivation) was up to 3-fold higher than CYP2D6 detoxification to PTP and MPTP-OH. Several N-methylated beta-carbolines and isoquinolines were screened for N-demethylation (detoxification) that was not significantly catalyzed by CYP2D6 or the P450s mixture. In contrast, various beta-carbolines were efficiently hydroxylated to hydroxy-beta-carbolines by CYP2D6. Thus, N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline (a close MPTP analog) was highly hydroxylated to 6-hydroxy-N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline and a corresponding 7-hydroxy-derivative. Thus, CYP2D6 could participate in the bioactivation and/or detoxification of these neuroactive compounds by an active hydroxylation pathway. The CYP2D6*1 enzymatic variant exhibited much higher metabolism of both MPTP and N(2)-methyl-1,2,3,4-tetrahydro-beta-carboline than the CYP2D6*10 variant, highlighting the importance of CYP2D6 polymorphism in the oxidation of these toxins. Altogether, these results suggest that CYP2D6 can play an important role in the metabolic outcome of both MPTP and beta-carbolines.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Alcaloides/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Dopaminérgicos/metabolismo , Harmina/análogos & derivados , Isoquinolinas/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacocinética , Biotransformação , Catálise , Cromatografia Líquida de Alta Pressão , Remoção de Radical Alquila , Dopaminérgicos/farmacocinética , Harmina/metabolismo , Humanos , Hidroxilação , Indicadores e Reagentes , Cinética , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Monoaminoxidase/metabolismo , Oxirredução , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Condujimos un estudio prospectivo descriptivo en la Clínica Anglo Americana, una institución privada que atiende a pacientes de estrato socio económico medio-alto en Lima metropolitana. El objetivo del estudio era determinar la frecuencia de hallazgos histológicos en biopsias hepáticas obtenidas por laparoscopía ó punción percutánea en pacientes con sobrepeso (IMC > 25 kg/m2) u obesos (IMC > 30 kg/m2), y evaluar la correlación con variables antropométricas como Indice de Masa Corporal (IMC), perímetro de cintura, historia de diabetes o dislipidemia y variables bioquímicas como glicemia, perfil lipídico, aminotransferasas y relación AST/ALT. Entre los años 2001 y 2006 se biopsiaron 50 pacientes, 29 con sobrepeso y 21 con obesidad. Dieciocho tuvieron esteatosis simple y 22 tuvieron Esteatohepatitis No alcohólica (NASH) (44 por ciento), de modoque 40 pacientes (80 por ciento) en total tuvieron alguna forma de hígado graso. Cinco pacientes (10 por ciento) tuvieron cirrosis confirmada por biopsia, y en todos ellos el hallazgo de cirrosis fue totalmente incidental. Un 64 por ciento de los pacientes con NASH fueron obesos, como lo fueron los cinco cirróticos de nuestra serie. Ilustramos en nuestro trabajo que en una muestra relativamente pequeña de pacientes con obesidad y sobrepeso como la obtenida, se encuentran todas las formas del espectro de la esteatosis hepática, que va desde la esteatosis simple hasta la cirrosis, con una gran frecuencia de NASH.
We conducted a prospective, descriptive study in the Clinica Anglo Americana, a prívate institution taking care of patients from a medium-high socioeconomic level in Lima. The goal of the study was to determine the frequency of histologic findings in liver biopsies performed by laparoscopy or percutaneously in patients with overweight (body massindex > 25 kg/m2) or obesity (body mass index > 30 kg/m2), and to evaluate the correlation with antropometric variables such as BMI, waist circumference, history of diabetes or hyperlypidemia, and biochemical variables like glycemia, lipid profile, aminotransferases and AST/ALT ratio. Between the years 2001 and 2006 50 patients were biopsied, 29 with overweight and 21 with obesity. Eighteen had simple steatosis and 22 had Non-alcoholic steatohepatitis (NASH) (44 per cent), so 40 patients (80 per cent) had some form of fatty liver. Five patients (10 per cent) had cirrhosis confirmed by biopsy, and in all of them the finding of cirrhosis wascompletely incidental. Sixty four percent of patients with NASH were obese, like the 5 cirrhotics in our series. Herein we illustrate that in a relatively small sample of patients with obesity and overweight like ours, we found all the forms of the liver steatosis spectrum,from simple steatosis to cirrhosis, with a high frequency of NASH.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Fibrose , Hepatite , Obesidade , Epidemiologia Descritiva , Estudos ProspectivosRESUMO
En la neuropatía epidémica, la carencia de estudios neurofisiológicos no ha permitido comprobar objetivamente daño de las fibras autonómicas. Este trabajo se propuso evaluar la función autonómica y utilizó una batería de pruebas basadas en reflejos cardiovasculares en pacientes. Se estudiaron 59 enfermos con los criterios clínicos establecidos por la OPS para el diagnóstico de la entidad. Se realizó un estudio con un grupo de 14 sujetos sanos y 45 pacientes. El 70 porciento de los casos presentaron algún tipo de alteración en la función autonómica cardiovascular. Las pruebas afectadas fueron: el equilibrio neurovegetativo basal en el 64 porciento de los pacientes y la integridad de la vía nerviosa vegetativa cardiovascular en el 36 porciento de ellos. Se detectaron diferencias significativas para las diferentes pruebas entre ambos grupos. Los resultados permiten afirmar que en la neuropatía epidémica existe una afectación importante en las fibras vegetativas cardíacas. El equilibrio neurovegetativo basal es una prueba sensible en el diagnóstico temprano de la entidad. Este método constituye en la actualidad una herramienta importante en el diagnóstico y evolución de la enfermedad, particularmente en los que requieren de peritaje médico
Assuntos
Humanos , Fenômenos Fisiológicos Cardiovasculares , Neurite (Inflamação)RESUMO
Se introduce una técnica más sensible para la evaluación funcional del tallo cerebral, aplicada a 51 pacientes afectados de hipertensión arterial esencial. Esta variante técnica consistió en el registro del potencial evocado auditivo del tallo cerebral con maniobra de giro del cuello. Las alteraciones halladas en pacientes sin manifestaciones clínicas de tipo vásculo-cerebral señalaron la importancia de este método para el diagnóstico precoz de la disfunción en el tallo cerebral cuando aún no existen evidencias clínicas, lo que le confiere un importante valor evolutivo y predictivo.
A more sensitive technique for the functional assessment of the brain stem, is introduced; it is applied to 51 patients affected with essential arterial hypertension. This technical variety consisted in recording the brain stem auditory evoked potential with a neck turn maneuver. The alterations found in patients without clinical manifestations of vasculocerebral kind, pointed out the importance of this method for an early diagnosis of the brain stem dysfunction, when there are not yet clinical evidences, which confers it an important evolutive and predictive value.