RESUMO
Histidine decarboxylase (HDC) is the single enzyme responsible for histamine synthesis. HDC-deficient mice (HDC(-/-)) have no histamine in their tissues when kept on a histamine-free diet. Therefore, the HDC(-/-) mice provide a suitable model to investigate the involvement of histamine in the regulation of histamine receptor expression. Gene expression of H1 and H2 histamine receptors was studied in several organs of HDC(-/-) mice and compared to standard (HDC(+/+)) mice. In many tissues, prolonged absence of histamine induced down-regulation of the H2 receptor subtype. The expression of the H1 receptor was less sensitive to histamine deficiency. Exogenous histamine present in the diet abolished the differences observed in H2 receptor expression. These results suggest that the expression of mouse H2 receptor is under the control of histamine in a tissue-specific manner.
Assuntos
Cimetidina/análogos & derivados , Regulação para Baixo , Histamina/metabolismo , Histidina Descarboxilase/deficiência , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismo , Animais , Cimetidina/metabolismo , Deleção de Genes , Perfilação da Expressão Gênica , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Camundongos , Camundongos Knockout , Especificidade de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant mechanisms referring to the role of histamine receptors, histidine decarboxylase and histamine release in the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, the better understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets.
Assuntos
Comunicação Autócrina/fisiologia , Substâncias de Crescimento/fisiologia , Histamina/fisiologia , Animais , Liberação de Histamina , Histidina Descarboxilase/metabolismo , Camundongos , Neoplasias/metabolismo , Ratos , Receptores Histamínicos/metabolismoRESUMO
In order to determine the role of endogenous histamine in the regulation of cell growth, the in vitro action of fluoromethyl-histidine (MFMH) was studied in experimental mammary carcinomas induced in rats. Tumor cells were cultured in soft agar using the clonogenic agar technique. The MFMH was added in different concentrations (0.01-100 microM). The effect observed was a 60% inhibition on colony formation with a maximal effect at concentrations over 10 microM. This action was completely reverted by the H2 agonists dimaprit and arpromidine with an IC50 value of 1 microM. The action of the H2 agonists when added alone was a significant increase in cell proliferation (135%), while the H1 agonist produced a dose-dependent inhibition on cell growth. In these experimental carcinomas endogenous histamine is critical for cell proliferation and one of its major effects may be the stimulation of cell growth by acting on specific H2 membrane receptors.
Assuntos
Carcinoma/patologia , Substâncias de Crescimento/fisiologia , Histamina/fisiologia , Neoplasias Mamárias Experimentais/patologia , Animais , Carcinoma/metabolismo , Feminino , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
The presence of H1 and H2 histamine receptors and their associated second messenger systems were studied during the development of the rat mammary gland. In the tissue of the young female, histamine presented a double receptor site as previously described for experimental mammary tumors, namely a high affinity H2 site (Kd = 10 +/- 2 nM, Bmax = 1068 +/- 71 fm/mg prot.), which mediated its effect via the products of phosphoinositide hydrolysis and a low affinity H1 receptor (Kd1 = 5 +/- 2 nM, Bmax = 188 +/- 33 fm/mg prot. and Kd2 = 41 +/- 20 nM, Bmax = 1980 +/- 790 fm/mg prot. when characterized with 3H-mepyramine), coupled to adenylyl cyclase activation. On the other hand, the mammary gland of the adult rat presented these receptors coupled to the classical second messenger systems described for mammalian cells, that is, the H2 receptor produced an increase in intracellular cAMP levels and the H1 receptor increased the phosphoinositide turnover. We conclude that histamine plays a critical role during development and differentiation of the normal rat mammary gland.