Qual a relação do café com o cortisolɁ
Um componente do café inibe a enzima que converte o cortisol inativo [cortisona] no ativo [cortisol]. O café sendo café. Sempre com açúcar.
[Imagem: domkofe.com.ua]
[Este artigo já foi publicado no nosso antigo blog do substack ao qual, recentemente,me foi vetado o acesso para postar novas publicações. Dessa forma e para que possa ser conhecido pelos leitores deste novo blog -intitulado outramedicina2024.substack.com - , faço aqui a republicação do artigo]
Muita gente está acostumada a repetir – naturalmente sem buscar se informar o suficiente a respeito – que tomar café aumenta o estresse. Que café aumenta o cortisol.
O café e suas propriedades já foi tema mais de uma vez neste blog. Nessas notas anteriores, foi esclarecido que o café não deve ser tomado sem açúcar. Sempre com açúcar [ou mel de abelha]. E que se a pessoa decide tomar sem açúcar melhor não fazê-lo, já que o café é um excelente alimento pró-metabólico e vai, por isso mesmo, demandar combustível, açúcar imediatamente. E criará um grau de estresse, pela falta do combustível que será demandado.
O estudo que comentaremos hoje vai nessa mesma direção.
Só que vai muito além.
Ele mostrou – de forma inédita e que, naturalmente não foi divulgada sistematicamente depois – que o café inibe a enzima que ativa o cortisol no nosso organismo. O estudo não se fixou na cafeína [uma importante substância adaptógena] e sim no café; e justamente, é o algo mais do café, são outras moléculas do café, que possuem tal efeito.
Existe uma enzima no nosso organismo, a 11beta-HSD1 [11-beta-hidroxisteroide deidrogenase tipo 1], cujo papel é converter o cortisol inativo [cortisona] no cortisol ativo. Pois bem, o estudo [A] mostrou que o café – veja bem, o líquido chamado café, não diretamente a cafeína, funciona como uma substância tireoide-like, impulsionador do metabolismo - ao inibir aquela enzima.
Dito de outra forma, o café detém a aparição do cortisol. Dose-dependente.
Quem toma café abraça um hábito contra o estresse, é elemento o que vem sendo argumentado de longa data por R. Peat.
Certamente a Big Pharma como argumenta o divulgador do trabalho [G Dinkov][B] pesquisa febrilmente um inbidor efetivo e seletivo daquela enzima [11beta-HSD1] para usar no tratamento farmacológico da obesidade, diabetes, Cushing, depressão e várias outras afecções. Pois bem, uma substância desconhecida e hidrossolúvel do café tem tal poder, inibe a produção de cortisol.
E que não é especificamente a cafeína, como foi argumentado acima. Aliás, mais de uma vez o próprio R. Peat argumentou que o café é muito mais que a cafeína. Naturalmente um café de qualidade.
E mais: café e cafeína revertem resistência insulínica e ajudam contra a obesidade, segundo estudos examinados já por Dinkov e destacados, pioneiramente, por R. Peat. Não é nosso tema aqui, hoje, em todo caso.
De toda forma, o estudo [A] é bem afirmativo: “um extrato de café, na concentração de 1% inibiu a enzima 11beta-HSD1 quase completamente” [A]. Demonstramos - continuam os pesquisadores - que o café inibiu, seletivamente e eficientemente a 11betaHSD1 e isso foi obtido também com extrato de cinco diferentes marcas comerciais de café. Mas não foi obtido com ácido cafeico ou com ácido clorogênico puro.
E a substância do café que tem aquele efeito anticortisol é termoestável, isto é, como mostraram os cientistas búlgaros, nem fervendo o café por 30 minutos se conseguiu anular o efeito antiestresse. No entanto, adicionar carvão no café, aí sim, aboliu tal efeito [A]. Também concluem que o estudo mostra de onde vem o efeito antidiabetogênico do café.
Ou seja, viria do seu efeito anti-cortisol.
Segundo os autores [A] pessoas com excesso de cortisol sistêmico são as que tendem a desenvolver obesidade visceral, obesidade, resistência insulínica, dislipidemia, hipertensão etc. Também se sabe que as catequinas e o epigalatocatequinagalato do chá verde [este com grande poder nesse sentido] possuem efeitos inibitórios sobre a 11beta-HSD1.
No argumento de G Dinkov, café [com açúcar] é uma boa maneira de baixar o estresse e também de perder peso, e estudo de 1920 mostrou perda de peso com a tomada de 10 cafés por dia [B].
A cortisona, quando não ativada, possui efeito glicocorticoide dez vezes menor que o cortisol. E cortisona é muito mais facilmente excretada na urina, outra razão pela qual a medicina opta pelo cortisol, farmacologicamente [G].
Sempre valendo levar em conta que o café é um estimulante metabólico. Isso é, certamente fará com que o ACTH aumente. O mesmo efeito da tireoide. O que demonstra, definitivamente, que estimular o metabolismo deve ser acompanhado do açúcar. Ou teremos efeitos colaterais...
Existe, portanto, uma armadilha no uso do café, isto é o café sem a adequada e simultânea nutrição pode ter efeito oposto ao do relaxamento, aumentando o cortisol.
A chegada do café mobiliza recursos [glicogênio, por exemplo] que podem não estar presentes naquele momento em que a pessoa acorda [após o jejum da madrugada] ou quando segue dieta sem açúcar [keto]. Os efeitos inibitórios do cortisol, próprios do café, estarão sendo bloqueados nesse caso. Há quem mencione a demanda de muito mais açúcar por cada café do que se pensa.
Para G Dinkov, a cafeína demora ao menos uma hora para alcançar seu pico máximo. Por sua vez, a chegada do açúcar no estômago já sinaliza [e também a partir da boca] alertando o cérebro para deter a produção de CRF e ACTH [estimulantes cerebrais do cortisol]; isto é, apesar da cafeína ser rapidamente absorvida, o açúcar age antes. E se for frutose [de um suco de laranja doce, por exemplo] agirá mais rapidamente ainda, provavelmente.
Mas a experiência pessoal é quem terminará batendo o martelo: há pessoas com saúde hepática ou renal ruim, problemas no eixo hipófise-tireoide-adrenal e, por razões alheias ao próprio café, podem apresentar uma reação de estresse ao seu consumo. Nesse caso há que investigar o problema. Personalizar o tema.
Por outro lado, receptores de açúcar do estômago/boca, por exemplo, podem estar relativamente neutralizados em quem fez cirurgia gástrica ou no nervo vago.
E o café traz vários outros nutrientes/adaptógenos. A niacinamida do café [talvez também o magnésio] tem o efeito parecido de deixar a pessoa relaxada, provavelmente por baixar o cortisol [semelhante ao de um benzodiazepínico].
Além disso, na explicação de Dinkov [B], a cafeína é dopaminérgica, um efeito benéfico que será perdido no tal café descafeinado.
E temos a testosterona. Como diz Dinkov, não é coincidência que homens que bebem café regularmente apresentem, usualmente, níveis de testosterona 30 % a mais que os mesmos da sua faixa de idade.
Por fim, uma curiosidade a favor do café [B]: enquanto o T3 pode ser inibido pelos óleos insaturados, por cortisol alto, a cafeína não, esta continuará agindo a despeito da presença deles.
A cafeína tem, então, um papel mais agudamente poderoso – a depender do contexto, claro – do que o T3, em dadas situações. Isso por um lado. Por outro lado, cafeína [e seu metabólito teacrina] aumenta a entrada de T3 nas células.
De tal forma, segundo Dinkov, que “tomar T3 com pequena dose de cafeína [muito pouco, tipo 50 mg] pode ajudar a contornar a inibição da entrada do T3 na célula pelos óleos insaturados”[B]. Valendo notar que os óleos insaturados também inibem a entrada de T4 nas células hepáticas [E].
De passagem é bom registrar que o azul de metileno [Dinkov], também terá dificuldade de entrar nas células quando há muito óleo insaturado presente no sistema; daí deve ser usado com um pouco de cafeína. Por outro lado, a captação de magnésio pelas células, a qual depende da adequada produção de ATP por estas, pode ser aumentada quando a pessoa usa café [cafeína, no caso].
Digamos que o café – para boa parte das pessoas – talvez deva ser entendido muito mais que um alimento, como sendo um superalimento. Daí como disse alguém, “this makes me fall in love with coffee even more”.
G Dantas [Publicado originalmente em Brasília, 21-5-24]
As informações aqui presentes não pretendem servir para uso diagnóstico, prescrição médica, tratamento, prevenção ou mitigação de qualquer doença humana. Não pretendem substituir a consulta ao profissional médico ou servir como recomendação para qualquer plano de tratamento. Trata-se de informações com fins estritamente educativos. Nenhuma das notas aqui presentes, neste blog, conseguirá atingir o contexto específico do paciente singular, nem doses, modo de usar etc. Este trabalho compete ao paciente com seu médico. Isso significa que nenhuma dessas notas - necessariamente parciais - substitui essa relação.
Referências _____________
[A] ATANASOV A G DZYAKANCHUK A A SCHWEIZER R A S, 2006.
Coffee inhibits the reactivation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: A glucocorticoid connection in the anti-diabetic action of coffee? FEBS Letters Volume 580, Issue 17, 24 July 2006, Pages 4081-4085 Edited by Robert Barouki https://doi.org/10.1016/j.febslet.2006.06.046Get rights and content
“Recent epidemiological studies demonstrated a beneficial effect of coffee consumption for the prevention of type 2 diabetes, however, the underlying mechanisms remained unknown. We demonstrate that coffee extract, corresponding to an Italian Espresso, inhibits recombinant and endogenous 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. The inhibitory component is heat-stable with considerable polarity. Coffee extract blocked 11β-HSD1-dependent cortisol formation, prevented the subsequent nuclear translocation of the glucocorticoid receptor and abolished glucocorticoid-induced expression of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. We suggest that at least part of the anti-diabetic effects of coffee consumption is due to inhibition of 11β-HSD1-dependent glucocorticoid reactivation.
1. Introduction
Coffee is one of the most often consumed beverages worldwide. Recently, several population studies demonstrated an association of coffee consumption with improved glucose tolerance and insulin sensitivity and a lower risk of type 2 diabetes [1], [2]. Constituents other than caffeine seem to be responsible for the anti-diabetic effects of coffee, however, neither the active compound nor the responsible target have been identified so far.
Based on a series of animal experiments and observations from studies with humans, it became evident that excessive glucocorticoid action plays a causal role in the pathogenesis of type 2 diabetes and metabolic syndrome [3], [4]. In particular, the enhanced local conversion of inactive 11-ketoglucocorticoids (cortisone, 11-dehydrocorticosterone) to active 11β-hydroxyglucocorticoids (cortisol, corticosterone) by 11β-HSD1 in metabolically active tissues such as liver, adipose tissue and skeletal muscle has been implicated in these disorders [5], [6], [7]. Whereas 11β-HSD1 knock-out mice were resistant to high fat diet-induced metabolic syndrome [8], [9], mice specifically overexpressing 11β-HSD1 in adipose tissue showed all typical features of the metabolic syndrome [10], [11]. Mice overexpressing 11β-HSD1 in the liver developed insulin resistance, dyslipidemia, and hypertension, but they were not obese [12]. Moreover, several studies reported an elevated 11β-HSD1 expression in adipose tissue of obese patients [5].
Treatment of obese and diabetic mouse strains with selective 11β-HSD1 inhibitors resulted in a significant improvement of glucose tolerance and insulin sensitivity, accompanied with reduced visceral fat deposits [13], [14], [15]. These studies suggest that inhibition or downregulation of 11β-HSD1 provides beneficial effects opposing the onset of metabolic syndrome [16].
We previously demonstrated the existence of natural compounds selectively inhibiting 11β-HSD1, e.g. flavanone and 2′-hydroxyflavanone present in red and yellow fruits and vegetables [17]. Because coffee is a rich source of biologically active compounds [18] and because of its anti-diabetic effect, we tested the hypothesis whether coffee contains compounds inhibiting 11β-HSD1 activity.
2. Materials and methods
2.1. Preparation of coffee extract
To prepare a coffee extract with a composition corresponding to that of an Italian Espresso, 10 g of freshly grinded roasted beans of Coffea Arabica L. were extracted with 30 ml of water for 15 s at 100 °C and a pressure of 15 bar. After sterile filtration, aliquots of the filtrate were frozen at −20 °C and stored until further analysis. To assess the effect of charcoal treatment on the inhibitory effect of the coffee extract, 10 ml of extract was incubated with 50 mg of activated charcoal for 10 min under stirring, followed by filtration. This procedure was repeated three times and the inhibitory potential of the stripped extract on 11β-HSD1 activity was measured. For the liquid/liquid extraction, 500 μl extract was mixed with 500 μl of the corresponding organic solvent (n-hexane, dichloromethane or ethyl acetate), followed by vigorous mixing for 10 s and incubation for 10 min. The water and organic phase were separated after centrifugation for 10 min at 10 000 × g.
3.1. Coffee extract inhibits 11β-HSD1 activity
To test our hypothesis that coffee beverage contains compounds with anti-diabetic effects due to decreased local glucocorticoid reactivation, we prepared a coffee extract with a composition similar to that of an Italian Espresso and tested its effect on 11β-HSD1-dependent conversion of cortisone to cortisol. The presence of coffee extract at a final concentration of 1% almost completely inhibited the 11β-HSD1-dependent oxoreduction of cortisone in cell lysates (Fig. 1). Upon incubation with various concentrations of coffee extract, a dose-dependent inhibition curve with an IC50 of approximately 0.25% was observed in cell lysates and of 0.7% in intact cells. Coffee extract similarly inhibited 11β-HSD1 activity in fully differentiated mouse 3T3-L1 adipocytes and in mouse C2C12 myotubes (not shown), two metabolically relevant endogenous cell models [24]. Inhibition of 11β-HSD1 was 7–10-fold more efficient than that of 11β-HSD2 and 17β-HSD1 (not shown), indicating that coffee preferentially inhibits glucocorticoid reactivation. Comparable results were obtained with five different commercially available coffee brands, while extracts from cocoa powder, which is also a rich source of polyphenolic compounds, did not inhibit 11β-HSD1.
3.2. Exclusion of caffeine as the 11β-HSD1 inhibitor
Next, we measured the effect of extracts from decaffeinated coffee on 11β-HSD1 activity and obtained an inhibition comparable to that of normal coffee extract. Moreover, 2 mM of pure caffeine did not affect 11β-HSD1 activity. We also found no inhibitory effect with 200 μM of caffeic acid, chlorogenic acid or trigonelline, three well-known biologically active substances present in coffee beverage (not shown).
3.3. Chemical properties of the inhibitory compound
We performed experiments to obtain initial information on the stability and polarity of the inhibitory compound. Boiling of the aqueous coffee extract for 30 min did not affect its effect, demonstrating that the inhibitor is thermo-stable (Fig. 2.). The inhibitory effect of the extract was abolished, however, upon charcoal treatment. To further assess the solubility of the inhibitor, the aqueous coffee extract was mixed with an equal volume of the organic solvents n-hexane, dichloromethane, or ethyl acetate, followed by separation of the two phases and determination of the presence of the inhibitory substance in both phases (Fig. 3). An equal partition was obtained with water/ethyl acetate, whereas highly hydrophobic solvents such as n-hexane extracted only small amounts of the inhibitor. These observations and the fact that it is solubilized from coffee beans with water suggest that the inhibitor is a fairly polar compound.
3.4. Blockade of 11β-HSD1-mediated GR activation by coffee extract
We tested the effect of coffee extract on the 11β-HSD1-dependent conversion of inactive cortisone to active cortisol and the subsequent induction of nuclear translocation of the GR. In the inactive state the GR resides in the cytoplasm. Upon binding cortisol it undergoes a conformational activation and translocates into the nucleus where it regulates genes with a GR-response element (GRE). As shown in Fig. 4, incubation of HEK-293 cells expressing GFP-GR and 11β-HSD1 with cortisone led to almost complete translocation of the receptor into the nucleus. Simultaneous incubation with coffee extract abolished nuclear receptor translocation, indicating inhibition of 11β-HSD1-dependent conversion of cortisone to cortisol. That the effect of coffee extract was due to inhibition of 11β-HSD1 is indicated by the lack of a direct effect of the extract to prevent cortisol-induced GR activation.
Furthermore, we assessed the effect of the inhibition of 11β-HSD1-dependent cortisol formation on the glucocorticoid-dependent expression of PEPCK (Fig. 5). Addition of 50 nM cortisone resulted in a 6-fold stimulation of PEPCK mRNA expression after a three hour incubation. Treatment of cells with increasing concentrations of coffee extract abolished glucocorticoid-induced PEPCK expression.
4. Discussion
A number of recent human population studies associated coffee consumption with a reduced risk for the development of type 2 diabetes [1], suggesting that coffee might be regarded as “functional food” for the prevention of metabolic disease [25]. However, little progress has been made so far in elucidating the mechanisms underlying the anti-diabetic effect of coffee drinking. It became clear that this effect is not related to caffeine itself, since consumption of decaffeinated coffee also exerted an anti-diabetic effect [26], [27]. Moreover, although for a long time most of the biological effects of coffee beverage have been referred to as pure caffeine effects, a recent study indicated that acute caffeine ingestion impairs glucose tolerance while regular consumption of caffeinated or decaffeinated coffee beverage exerts a protective effect against type 2 diabetes [28].
Some biologically active ingredients of coffee that were suggested to contribute to its anti-diabetic actions are chlorogenic acid – through reduced glucose absorption and increased production of glucagon-like peptide 1 [29], lignans – through antioxidant and estrogenic activity [30], and trigonelline, which was shown to lower blood glucose levels by yet unknown mechanisms. However, none of these ingredients seems to be responsible for the anti-diabetic effects of regular coffee intake [2].
It is generally accepted that excessive glucocorticoid action plays an important role in the pathogenesis of obesity and type 2 diabetes. Many features of the metabolic syndrome are observed in patients with Cushing’s syndrome due to excessive glucocorticoid production as a result of adrenal tumors or because of prolonged treatment with high pharmacologic doses [31]. In obese individuals, however, systemic glucocorticoid levels are not significantly elevated, but an increased local reactivation of glucocorticoids in adipose tissue and in skeletal muscle has been associated with the pathogenesis of the metabolic syndrome [32]. Importantly, recent studies demonstrated a significant improvement of glucose tolerance and insulin sensitivity in obese and diabetic animals treated with synthetic 11β-HSD1 inhibitors [13], [14], [15].
We previously reported the existence of natural compounds inhibiting 11β-HSD1 [17]. Flavanone and 2′-hydroxyflavanone, present in red and yellow fruits and vegetables, inhibited 11β-HSD1 oxoreductase activity in lysates and intact cells without inhibiting the related enzymes 11β-HSD2, 17β-HSD1 or 17β-HSD2. A recent in silico screening of a library of 114 000 natural compounds conducted by researchers at the Nestle Research Center yielded several flavanone derivatives, not specified further, that fitted into the substrate-binding pocket of 11β-HSD1 [33]. Coffee is an extraordinarily rich source of biologically active compounds, however, only very few compounds have been studied more extensively so far.
The present study suggests the presence of a thermo-stable substance with considerable polarity – a profile that suits a polyphenolic or flavonoid-like compound. Our results clearly demonstrate the presence of relevant amounts of compound(s) in coffee beverage that inhibit 11β-HSD1-dependent reactivation of glucocorticoids, thereby reducing the activation of the GR. Moreover, using a liver cell model, we provide evidence that coffee-induced inhibition of 11β-HSD1 decreases hepatic gluconeogenesis. Nevertheless, further experiments are required to identify the compound(s) responsible for the observed effects and to test their effects on glucose tolerance and insulin sensitivity in vivo.
Acknowledgements
We thank Heidi Jamin for excellent technical support. This work was supported by grants from the Cloëtta Research Foundation and the Swiss National Science Foundation Grant No. 310000-112279 and No. 4050-066575 (NRP50 “Endocrine disruptors”).
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Individuals with systemic glucocorticoid excess develop visceral obesity, insulin resistance, glucose intolerance, dyslipidemia, hypertension, etc (Hollis and Huber, 2011). Even though there is not much research on polyphenols effect on 11b-HSD1 protein, a study with Italian espresso coffee extract showed the inhibition of recombinant and endogenous 11b-HSD1 dependent cortisol development activity, the prevention of the consequent nuclear translocation of the glucocorticoid receptor and the eradication of glucocorticoid-induced expression of the enzyme phosphoenolpyruvate carboxykinase (Atanasov et al., 2006). Another study demonstrated that catechins and (-) Epigallocatechin gallate from green tea, exhibited the highest inhibitory potential of 11b-HSD1 activity with an IC50 value of 3.749 mg of dried tea leaves per ml.
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2010, Osteopathic Family Physician
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Other compounds have also been shown to affect 11β-HSD activity as well. For example, both caffeinated and decaffeinated coffee extracts inhibit 11β-HSD and inhibit reduction of cortisol to cortisone.19 Licorice derivatives glycyrrhizic acid and glycyrrhetinic acid are also potent inhibitors of 11β-HSD, and their proposed mechanism of action is inhibition of the mRNA coding for 11β-HSD, which has been shown to increase the activity of glucocorticoids in rats (Fig. 3).20
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2009, Fitoterapia
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2008, Biochemical Pharmacology
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Natural compounds may also ameliorate adverse glucocorticoid effects by decreasing 11β-HSD1-dependent conversion of cortisone to cortisol. Several compounds including glycyrrhetinic acid, abietic acid, flavanone and constituents in roasted coffee beans were found to inhibit 11β-HSD1 [23,24]. Based on these recent observations, we hypothesize that the modulation of glucocorticoid responses by environmental chemicals may allow an organism to coordinate its physiological processes and adapt to changes in the environment, such as food availability and composition. Show abstract
Disponivel em: https://www.sciencedirect.com/science/article/pii/S0014579306007538
[B] G Dinkov - https://raypeatforum.com/community/threads/coffee-inhibits-cortisol-synthesis.11138/
[C] GERSPACH A C STEINERT R E, 2011. The role of the gut sweet taste receptor in regulating GLP-1, PYY, and CCK release in humans. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E317-25. doi: 10.1152/ajpendo.00077.2011. Epub 2011 May 3. PMID: 21540445 DOI: 10.1152/ajpendo.00077.2011 “The recent identification of sweet taste receptors in the gastrointestinal tract has important implications in the control of food intake and glucose homeostasis. Lactisole can inhibit the sweet taste receptor T1R2/T1R3. The objective was to use lactisole as a probe to investigate the physiological role of T1R2/T1R3 by assessing the effect of T1R2/T1R3 blockade on GLP-1, PYY, and CCK release in response to 1) intragastric administration of nutrients or 2) intraduodenal perfusion of nutrients. The study was performed as a randomized, double-blind, placebo-controlled crossover study that included 35 healthy subjects. In part I, subjects received intragastrically 75 g of glucose in 300 ml of water or 500 ml of a mixed liquid meal with or without lactisole. In part II, subjects received an intraduodenal perfusion of glucose (29.3 g glucose/100 ml; rate: 2.5 ml/min for 180 min) or a mixed liquid meal (same rate) with or without lactisole. The results were that 1) lactisole induced a significant reduction in GLP-1 and PYY but not CCK secretion in both the intragastric and the intraduodenal glucose-stimulated parts (P ≤ 0.05), 2) comparison of the inhibitory effect of lactisole showed a significantly greater suppression of the hormone response in the intragastric part (P = 0.023), and 3) lactisole had no effect on liquid meal-stimulated parameters. We conclude that T1R2/T1R3 is involved in glucose-dependent secretion of satiation peptides. However, the results of the liquid meal-stimulated parts show that the receptor alone is not responsible for peptide secretion.
[D] RIMSON J, 1977. Caffeine. Mutat Res. 1977;47(1):1-52. doi: 10.1016/0165-1110(77)90016-1. PMID: 342928 DOI: 10.1016/0165-1110(77)90016-1 “Most of the population of the world is exposed to caffeine to a greater or lesser extent since it occurs in a number of plants used in the preparation of widely consumed drinks, and has in addition a limited therapeutic use. Chromosomal abnormalities are induced by caffeine in both plant cells and in mammalian cells in culture and it also has some anti-mitotic activity. DNA-repair processes sensitive to caffeine have been demonstrated in a number of cell systems and it has been shown to affect a wide range of other cellular processes. Caffeine has potent mutagenic effects in Escherichia coli and other micro-organisms both when acting alone and in combination with other mutagens. However its mutagenic activity in Drosophila has been disputed and the available evidence suggests that it is neither mutagenic in mammals nor synergistic with other mutagens although at very high doses it appears to have some teratogenic activity in mammals”. A cafeína é acusada de causar efeitos mutagênicos, mas em mamíferos é necessário que as doses sejam muito mais altas que as habituais. E não está claro o contexto, isto é, se outras substâncias precisam ser associadas à cafeína para que ela tenha tal efeito.
[E] HANNEMANN G DOCTER R FRIESEMA E C H, 2001. Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability Endocrine Reviews, Volume 22, Issue 4, 1 August 2001, Pages 451–476, https://doi.org/10.1210/edrv.22.4.0435 Published: 01 August 2001 “Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis- Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level”.
[G] G Dinkov citando a Wikipedia.
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