Page 1 of 8 Critical review Nutrition-dependent GABA deficiencies in endocrine pancreas causes cancer, as shown for betel nut consumers and for diets de-activating vitamin B6 Basic Cancer Biology M Israël* Abstract 6 - Introduction We earlier proposed, via a published de-activating vitamin B include pel GABA in the extracellular space and- lagra, a niacin deficiency due to maize take it up when2 GABA levels decrease 6 diet; there, amines form adducts with- in the cell, terminating the transmit hypothesis, that deficient cellular vitamin B and may increase the risk ter action . In endocrine pancreas, - 6 - interactions in endocrine pancreas for cancer. Another adduct is a vi beta cells that release insulin switch- causes cancer. These deficient in tamin B -pyrrole compound found off the alpha and delta cells, contain teractions result from a perturbed in Prolinemia type II. Thus, for the ing glucagon and somatostatin, re gamma-aminobutyric acid (GABA) carcinogenic pyrrolizidines present spectively, with GABA. At rest, GABA release by beta cells that are unable to- in Boraginaceae and other plant is constantly released by beta cells, inhibit neighbouring alpha and delta families, pyrroles resulting from the by the transporters, and poured over 6 - cells. Consequently, a hybrid cata degradation of pyrrolizidines form a the alpha and delta cells, acting on-– bolic–anabolic metabolism, mediated pyrrole-vitamin B adduct, which ex- GABA A receptors. An influx of Cl by glucagon and insulin, takes place. plains their carcinogenicity. This is- through these receptors hyperpo The catabolic and anabolic hormones applicable to other pyrrole-contain larizes alpha and delta cells, which - 6 supple- - act via kinases and phosphatases on- ing drugs and to diseases with pyr keeps the+ glucagon and somatostatin specific enzymatic switches, thus re roluria. Moreover, vitamin B release silent. Beta cells sense glycae- Conclusion ATP wiring metabolic pathways and giv mentation seems to prevent cancer. mia via K channels (K ), which are ing mitotic cells a special advantage, - inhibited by ATP. Hypoglycaemia+ de- leading to cancer. The pancreatic The aim of this review is to discuss creases cellular ATP and opens these GABA starter hypothesis for cancer how nutrition-dependent GABA defi- channels; the resulting K efflux hy seems verified on a large population- ciencies in endocrine pancreas could perpolarizes beta cells and GABA is of regular consumers of palm tree cause cancer in betel nut consum retained. Because the alpha cells are - 6 - betel nuts. These nuts contain clas ers and in those on diets with low no longer inundated by GABA, they sical GABA inhibitors that affect pan Introductionvitamin B . consequently release glucagon in re- creatic mechanisms; epidemiological Areca catechu - sponse to hypoglycaemia. If nipecotic- studies on large populations of betel acid blocks the inward GABA trans nut consumers have shown that they is a palm tree that pro port, then the immediate effect in 6 are at an increased risk for cancer.- duces betel nuts, which have been volves an increase in extracellular Because vitamin B is a cofactor of consumed in Asia, including India, GABA levels; however, in the long run,- glutamate decarboxylase, GABA syn by millions of people for centuries. the resting efflux of GABA declines, 6 - thesis should decrease in processes- Among the alkaloids found in betel- as the poor recovery of extracellu de-activating vitamin B , thereby in nuts, arecoline, the most abundant, is- lar GABA tends to deplete the GABA creasing the riskGyromitra for cancer. esculenta Gyromi a nicotinic acid ester and a choliner cell content. The blockade of alpha trin, a hydrazine found in a consumed gic agonist. Other nicotinic acid alka and delta cells by beta cells becomes 6 mushroom ( ), loids include arecaidine, guvacoline, gradually less efficient. Glucagon2,3 and forms vitamin B -hydrazones; these guvacine and nipecotic acid, which somatostatin are then released even de-activate the vitamin. Gyromitrin is inhibit gamma-aminobutyric acid when insulin secretion operates . A carcinogenic in rodents. Pathologies (GABA) transporters. In addition, hybrid mixed metabolism gradually these alkaloids1 seem to bind to GABA takes over; it associates glucagon- A receptors, resulting in competition- mediated effects, mobilizing body- with GABA . - stores via catabolic hormones, and * Corresponding author It is to be recalled that GABA trans insulin actions that mediate anabo- Email: [email protected] porters are driven by the concentra lism, particularly in mitotic cells that 2 Av. Aristide Briand 91440 Bures sur Yvette, tion of GABA. If cytosolic GABA levels renew tissues. This metabolic situa France Licensee OA Publishing Londonare elevated,2013. Creative transporters Commons release Attributiontion is supposed License to (CC-BY)be carcinogenic, Israël M. for betel nut consumers and for diets de-activating vitamin B6 For citation purposes: Nutrition-dependent GABA deficiencies in endocrine pancreas causes cancer, as shown none declared. interests: none declared. Conflict of interests: Competing the final manuscript. preparation, read and approved and design, manuscript conception to All authors contributed rules of disclosure. ethical Ethics (AME) for Medical the Association All authors abide by . OA Cancer 2013 May 01;1(1):2. Page 2 of 8 Critical review as proposed by us in a recent review- entitled ‘A possible primary 3cause- of cancer: deficient cellular interac tions in endocrine pancreas’ . Un fortunately, this hypothesis seems to be validated on millions of people in Asia, including India; these people- have been consuming betel nuts for centuries. Indeed, recent epidemio logical studies show that cancer risk4,5 is greater for betel nuts consumers . Cancers of the mouth and digestive6 - tract, as well as the liver, or breast cancers are more frequent . Fortu nately, betel nuts are often consumed with leaves of another plant—a climbing vine, piper betel (not to be confused with betel nut palm tree). Piper betel leaves have anticancer properties owing to the presence of- antioxidant and anti-inflammatory- compounds—eugenol, hydroxychav icol and alpha to copherol. In addi tion, betel nut eaters live in countries where rice is a major diet and rice is particularly rich in GABA, perhaps protecting the betel nut consumers against cancer? Figure 1: Carcinogenic betel nuts affect pancreatic GABA as does diets that The fact that betel nut consumers de-activate vitamin B6 have more cancers seems to validate- the ‘grandeur nature’ postulated by . Many people consume betel nuts; these contain arecaidine, the hypothesis—the metabolic re guvacine and nipecotic acid which block GABA interactions in endocrine pancreas. wiring found in cancer starts with a Beta cells release insulin, but their GABA release gradually gets exhausted, thereby pancreatic deficiency in which beta failing to inhibit alpha and delta cells, releasing glucagon and somatostatin, cells become unable to control alpha respectively. The hypothesis, which considers that cancer results from this 6 - and delta cells. deficient GABA interaction in pancreas, seems validated by epidemiological works In addition, vitamin B pyridoxalde on large populations of betel nut consumers. The figure also analyses the possible hyde, which is a cofactor of glutamate effects of maize diets (transgenic or wild-type) on GABA synthesis in relation to decarboxylase (GAD), forms inactive pellagra. In vegetal, the enzymeAgrobacterium for aromatic amino-acidtumefaciens synthesis 5-enolpyruvyl- adducts with a variety of amines, shikimate-3-phosphate synthetase (EPSPS) is inhibited by glyphosate. An enzyme which decreases the synthesis and resistant to glyphosate from was used for producing release of GABA from beta cells and transgenic maize. EPSPS initiates the synthesis of tryptophan,+ leading to auxin, suppresses the inhibition1 of alpha a growth hormone inducing callosities in agrobacterium-infected plants. Maize metabolism+ is special; little tryptophan goes to niacin and NAD , causing pellagra and delta cells, thus aggravating the 6 in populations consuming maize diets. Leucine aggravates pellagra by inhibiting carcinogenicDiscussion process (Figure 1). 6 NAD synthesis; this is cancelled by vitamin B , thereby conferring protection from pellagra. Maize indolamines react with vitamin B aldehyde and deactivate the 6 The author has referenced some vitamin favouring pellagra. Native cultivators avoided pellagra by nixtamalization. 6 of his own studies in this review. Another consequence of vitamin B deficiency is the inhibition of glutamatede These referenced studies have been carboxylase; similar vitamin B deactivations occur with hydrazines found in some conducted in accordance with the mushrooms (gyromitrin) or with pyrroles formed in various other conditions. Declaration of Helsinki (1964), and Furthermore, an insecticide fipronil is known to inhibit GABA A receptors and the protocols of these studies have provoke thyroid cancer in rats. A decreased GABA synthesis, release or action in been approved by the relevant ethics pancreas increases the risk for cancer. Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY) Israël M. for betel nut consumers and for diets de-activating vitamin B6 For citation purposes: Nutrition-dependent GABA deficiencies in endocrine pancreas causes cancer, as shown none declared. interests: none declared. Conflict of interests: Competing the final manuscript.