Alteration in glucose metabolism in the brain associated with tamoxifen treatment: Study in postmenopausal animal model.

Tamoxifen is an effective breast cancer therapy in postmenopausal women. However, it can induce hyperglycemia through different mechanisms, such as the impairment of mitochondrial metabolism. Quercetin, a flavonoid with antioxidant potential, has beneficial effects on tamoxifen-induced adverse effects. Therefore, this study aimed to (1) investigate glucose concentration in blood, cerebrospinal fluid, cerebellum, cortex, and hippocampus of tamoxifen-treated ovariectomized female rats, non-treated and treated with quercetin; and (2) establish the metabolic profile of these regions. For that purpose, ovariectomized female rats were divided into four groups: canola oil 1 mL/kg (CONT); tamoxifen 5 mg/kg (TAM); quercetin 22.5 mg/kg (QUER); and tamoxifen 5 mg/kg + quercetin 22.5 mg/kg (TAM + Q); and were treated for 14 days orally. Subsequently, glucose levels were measured in blood, cerebrospinal fluid, cerebellum, cortex, and hippocampus. Pyruvate and lactate concentrations were analyzed in the three brain regions. Tamoxifen-induced hyperglycemia significantly increased glucose concentrations in the cerebrospinal fluid, cortex, and hippocampus, as well as lactate production in the hippocampus. Quercetin significantly prevented the tamoxifen-induced increase in glucose concentrations in all analyzed samples. Besides, quercetin decreased cortical pyruvate production. The copper content decreased only in the hippocampus of group TAM + Q animals. In addition, it is important to highlight that this study also observed that fourteen days of tamoxifen treatment strongly affects brain glucose metabolism, potentially disrupting normal brain functions. Therefore, this drug might represent a risk factor for postmenopausal women undergoing chemoprevention. Meanwhile, quercetin represents a potential intervention to promote metabolic regulation of glucose in tamoxifen-treated women.

Antihyperglycemic Effect of Quercetin in Ovariectomized Rats Treated with Tamoxifen.

Tamoxifen is effective in breast cancer therapy in postmenopausal women; however, it causes adverse effects that alter the glycolytic pathway and induce hyperglycemia. Quercetin, a flavonoid with antioxidant potential, inhibits butyrylcholinesterase (BuChE), which is positively associated with hyperglycemia. Therefore, this study investigated the effect of quercetin on tamoxifen-induced hyperglycemia, using BuChE activity as a bioindicator in adult ovariectomized Wistar rats. The ovariectomized rats were treated orally for 14 days with different concentrations of quercetin (2.5, 7.5, 22.5, and 67.5 mg.kg-1 b.w.) and tamoxifen (5 mg.kg-1 b.w.). Subsequently, they were euthanized; blood and tissue samples were collected. The following biochemical parameters were analyzed: plasma glucose levels and BuChE activity in the plasma, liver, intestine, and adipose tissue. The most effective dose of quercetin in reducing hyperglycemia was 22.5 mg.kg-1 b.w. (Que/TAM 4.5/1, P < .00000), although the doses of 2.5 (Que/TAM 0.5/1, P < .05) and 7.5 mg.kg-1 b.w. (Que/TAM 1.5/1, P < .05) were also effective. The BuChE activity decreased in the intestine at all tested doses of quercetin coadministered with tamoxifen (P < .01); however, in adipose tissue, there was a biphasic activity with a decrease (P < .05) and increase (P < .05) in activity at doses of 7.5 and 22.5 mg.kg-1 b.w. of quercetin, respectively. However, the correlation between BuChE and glucose levels was not significant (P > .05). In summary, the findings of the present study suggest that quercetin when associated with tamoxifen decreases in plasma glucose levels. Furthermore, in these cases, BuChE should not be used as an indicator of hyperglycemia.

Influence of the Alcohol Present in a Phytotherapic Tincture on Male Rat Lipid Profiles and Renal Function.

This study evaluated the influence of the alcohol present in a formulation of the antiophidic phytotherapic tincture, Específico-Pessôa, on rat blood biochemical and hematological parameters, and on organ histology. Three groups of rats were treated orally for 10, 15, or 30 days; one group received the tincture, the other received alcohol alone, and the third was a control group. The results of this study indicated that cholesterol levels were significantly increased after 10 days in the alcohol and tincture groups, although these decreased after 30 days in the tincture group. Triglyceride levels were significantly reduced after 15 days in the tincture group and after 30 days in the alcohol and tincture groups. A higher creatinine level was observed in the alcohol and tincture groups after 15 and 30 days. The uric acid levels in these groups were reduced at 10 and 30 days, although this metabolite was elevated at 15 days in the alcohol group. Hydropic multifocal degeneration with lymphohistiocytic infiltration and some polymorphonuclear cells was observed in the livers of rats treated with either the tincture or alcohol. These data demonstrate the importance of considering the potential actions of the alcohol present in pharmaceutical formulations.

Influence of tamoxifen on gluconeogenesis and glycolysis in the perfused rat liver.

The actions of tamoxifen, a selective estrogen receptor modulator used in chemotherapy and chemo-prevention of breast cancer, on glycolysis and gluconeogenesis were investigated in the isolated perfused rat liver. Tamoxifen inhibited gluconeogenesis from both lactate and fructose at very low concentrations (e.g., 5µM). The opposite, i.e., stimulation, was found for glycolysis from both endogenous glycogen and fructose. Oxygen uptake was unaffected, inhibited or stimulated, depending on the conditions. Stimulation occurred in both microsomes and mitochondria. Tamoxifen did not affect the most important key-enzymes of gluconeogenesis, namely, phosphoenolpyruvate carboxykinase, pyruvate carboxylase, fructose 1,6-bisphosphatase and glucose 6-phosphatase. Confirming previous observations, however, tamoxifen inhibited very strongly NADH- and succinate-oxidase of freeze-thawing disrupted mitochondria. Tamoxifen promoted the release of both lactate dehydrogenase (mainly cytosolic) and fumarase (mainly mitochondrial) into the perfusate. Tamoxifen (200µM) clearly diminished the ATP content and increased the ADP content of livers in the presence of lactate with a diminution of the ATP/ADP ratio from 1.67 to 0.79. The main causes for gluconeogenesis inhibition are probably: (a) inhibition of energy metabolism; (b) deviation of intermediates (malate and glucose 6-phosphate) for the production of NADPH required in hydroxylation and demethylation reactions; (c) deviation of glucosyl units toward glucuronidation reactions; (d) secondary inhibitory action of nitric oxide, whose production is stimulated by tamoxifen; (e) impairment of the cellular structure, especially the membrane structure. Stimulation of glycolysis is probably a compensatory phenomenon for the diminished mitochondrial ATP production. The multiple actions of tamoxifen at relatively low concentrations can represent a continuous burden to the overall hepatic functions during long treatment periods.

Padronização de spot tests para uso em laboratórios com atendimento em emergências toxicológicas / Using stardardization spot tests in laboratories with toxicological emergencies service

A padronização de métodos simples e confiáveis em laboratórios de análises clínicas que atuam em emergências toxicológicas é importante, visto o alto índice de intoxicações apresetnado nas mais diversas regiões do país. Dentre as intoxicações, as de maior destaque são as medicamentosas. Os medicamentos mais envolvidos são os analgésicos, os benzodiazepínicos e os barbitúricos (fenobarbital). Assim foram padronizados alguns spot tests, segundo Brito Filho, para a pesquisa destes medicamentos em sangue e urina. Os resultados mostraram-se satisfatórios, com valor de sensibilidade de 0,1 e 0,3mg/mL, consistindo em provas simples, rápidas, de baixo-custo e de fácil implantação em laboratórios clínicos.