Nutrition-Dependent GABA Deficiencies in Endocrine Pancreas Causes Cancer, As Shown None Declared

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 3 cause- 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

Critical review

committees related to the institution of maize causes niacin deficiency,- adducts, which are perhaps disso in which they were performed. All leading to a severe disease known- ciated in alkaline conditions. Thus, human subjects, in these referenced as pellagra. This disease killed thou when maize is the major diet, niacin 6 studies, gave informed consent to sands of poor people along the Mis- (vitamin PP) deficiency is associated Maize:participate The in fear these of cancerstudies. after the sissippi river and then in Europe, in with a deficiency of vitamin B ; these- curse of pellagra the Landes, when maize was intro deficiencies are attenuated if maize duced. Joseph Goldeberger (1874– is nixtamalized. The undesired con 6 - - 1929) discovered that pellagra was- sequence of this additional vitamin Glyphosate (roundup) is an inhibitor a deficiency disease, a disease of B loss is the inhibition of decarboxy 6 of 5-enolpyruvyl-shikimate-3-phos poverty, affecting populations es lases, such as GAD, requiring vitamin- phate synthase (EPSPS). This enzyme- sentially eating maize. We now know B . The synthesis of GABA should initiates the synthesis of aromatic that pellagra results from a poor then decrease in relation to this in 3 amino acids (tyrosine, phenylala tryptophan conversion into niacin,- trinsic property of maize—at least nine and tryptophan) in plants and also named vitamin B or vitamin PP when maize becomes the major diet. bacteria. A mutant EPSPHAgrobacterium enzyme, for pellagra preventis (Figure 1). Pel Moreover, it has been observed that tumefacienswhich is resistant to glyphosate, has lagra became more frequent when glyphosate15 itself alters GABA ergic- been discovered in maize was directly milled, rather neurons . - . The mutant EPSPS gene than treated, like native cultivators A maize diet leads to pellagra pro - 6 of agrobacterium was subsequently had empirically discovered. Native voked by niacin deficiency; an associ used for producing transgenic maize- cultivators cooked maize first in al- ated vitamin B loss should also elicit- tolerant to glyphosate and cultivated7,8 kaline solutions (initially ashes) and neurological troubles, dementia or- in conditionsA. tumefaciens that eliminate unde- then in calcium hydroxide; this pro epilepsy, as GABA is a major trans sired weed sensitive to glyphosate . cedure was named nixtamalization10 mitter in the central nervous sys In nature, is attract- (from 11,12an Aztec word) . It is believed- tem. This effect may be exacerbated ed by wounded plants and injects a that this procedure releases bound by drugs such as glyphosate, which - 6, strand of its plasmidic DNA express niacin or other anti-pellagrogen interferes with glutamate/aspartate ing the mutant EPSPS gene and oth ic substances, such as vitamin B processes, thereby inhibiting GAD. In 6 er genes in the plant. The bacterial from indolamine adducts. Indeed, principle, a lower pancreatic GABA genes are incorporated into the plant tryptophan is an essential+ amino synthesis resulting from vitamin B genome and control the synthesis of acid for animals; it forms niacin+ inis deficiency is possible; 3 this would- tryptophan and derivatives leading the liver and then NAD . One of the elicit a hybrid anabolism/catabolism,- to auxin, a plant growth hormone. key enzymes synthetizing NAD which may cause cancer . This find 6 6 Auxin elicits local tumour callosities inhibited by leucine, and this effect ing is in agreement with16 epidemio in the infected plant. In the callosity,- pellagrais cancelled13 by vitamin B , which- logical observations on vitamin B the secretions of various cytokines then protects from leucine-induced deficiencies and cancer . However, if (octopine and nopaline) that are ar (Figure 1). In maize, in the maize diet is dangerous, pellagra 6 6 ginine derivatives9 are beneficial to- dolamines probably react with the is the initial danger, associated with- the bacteria . aldehyde radical of vitamin B and- niacin deficiency; an associated B One may expect that transgen de-activate this vitamin; this is also loss would produce, via GAD, neuro 6 - ic maize expressing the bacterial- true for some drugs producing hy edlogical17 troubles, before being ‘in fine’ EPSPS enzyme displays an active drazones with vitamin B . We know,- carcinogenic, as recently suspect tryptophan biosynthesis, as this en- for example, that patients treated . The properties of glyphosate zyme initiates the pathway leading with isoniazid (a nicotinic anti-tu that would be accidentally absorbed18 6 - , sug- from tryptophan to auxin in agro berculosis drug) have to take much- deserve more studies; it elicits an- bacterium. Unfortunately, in maize more vitamin B to prevent14 symp increased glycaemia in fishes - 6 (transgenic or wild-type), very little- toms recalling pellagra . The indola gesting a pancreatic effect and a pos tryptophan is left for another path mine-vitamin B reaction is relevant- sible pancreatic GABA deficiency. On way, leading to the synthesis of nico for transgenic maize, as the bacterial the other hand, glyphosate may have, tinic acid (niacin). In maize, most gene orients the biosynthesis of aro in addition to its interesting anti- tryptophans rather produce indolic- matic amino acids from tryptophan weed effects, insecticide properties, derivatives and indolamines, which towards indolic amines instead of affecting glutamatergic transmission are poor niacin precursors. In ani niacin. The indolamines and other of insect neuromuscular synapses. 6 mals and humans fed essentially on tryptophan derivatives de-activate Specific metabolic properties of a maizeLicensee diet, low tryptophan OA Publishing content London vitamin 2013. B , forming Creative amine-aldehyde Commons Attributionmaize led License native cultivators (CC-BY) to treat

Israël M. for betel nut consumers and for diets de-activating vitamin B6

2+ - 6 ad- maize with an alkaline procedure that- physiology2+ of beta cells; they release base or hydrazone de-activations.- protected them from pellagra. We in- Zn in parallel to GABA, and the loss This special pyrrole vitamin B deed know that niacin was the miss of Zn affects inhibitory controls of- duct has been identified in a rare in- ing vitamin and pellagra has disap beta3 cells over neighbouring cells, herited disorder—hyperprolinemia peared. If the17 tumourigenic effects of inducing a possible carcinogenic pro- type II—due to the lack of delta-pyr maize (transgenic or wild-type) were- cess . roline-5-carboxylate dehydrogenase. confirmed , it would indicate that a We also know that several veg- The lack of this enzyme results in the maize diet adds up to the known nia etal families rich in pyrrolizidine- upstream accumulation of pyrroline- cin deficiency, a B6 deficiency acting alkaloids are tumourigenic; the pyr 5-carboxylic acid and its reduced - 6 on pancreatic mechanisms that can- rolizidines are degraded into pyr pyrrolidine derivative, proline, which lead to cancer. These deficiencies ap roles that bind to vitamin B20–22; this is gets elevated in the blood. It is the- pear when maize becomes the ma- Carcinogenicdiscussed in the pyrrolizidine next section . C4 carbon of the oxidized pyrroline-- jor diet—they result from intrinsic 5-carboxylic acid that forms a cova alkaloids 6 6 properties of maize metabolism, ex lent link with the carbonyl of vita acerbated if maize is uncooked or not min B ; this new pyrrole-B adduct23 - 6 Pyrroluria-associatedsupplemented with missing diseases vitamins. There are other known carcinogenic is well characterized, giving another - alkaloids, such as pyrrolizidines, es- process for deactivating vitamin B ; - sentially found in Boraginaceae, but this explains the carcinogenicity of In line with the aforementioned de they are also found in some Asterace Tumourigenicityalkaloids degraded of into Gyromitra pyrroles. scription, we should mention sev ae or Fabaceae families. Crotalaria, 6 Senecio jacobaea, esculenta: Vitamin B6 de- eral pathologies in which vitamin- Symphytumfor example,20 officinale can contaminate or Senecio maize rid- activation of GABA synthesis B losses associated with pyrroluria- delliicrops . Further, - are occasionally observed (schizo- - phrenia, Down’s syndrome, haemo alkaloids are dangerous. Pyr- Gyromita mushrooms contain a toxin lytic diseases and familial pyrrolu rolizidine alkaloids are characterized named gyromitrin, a hydrazine de 6 ria). An increased degradation of by the necine ring21,22 (resembling a dou rivative that forms hydrazones with biological constituents2+ into pyrroles ble pyrrolidine), and their catabolism vitamin B , as mentioned above for 6 - favours their reaction with vitamin forms pyrroles that are excreted isoniazide, an anti-tuberculosis drug. 6 - B and Zn , a complex is excreted in bile or urine. They may again bind Acute intoxication results in con24,25 in urine. Pyrroluria was discovered vitamin B and change the pancre vulsions, liver injury and death . on urine chromatograms of patients atic physiology of GABA, leading to When low doses of this toxin were- as a ‘mauve spot’ or kryptopyrrole,19 the development of cancer in the- injected26 into rodents, they resulted stained with Erlich’s reagent . The long run. Much work remains to be in liver carcinomas and adenocarci 6 formation of aldehyde adducts with done on pyrrolizidine carcinogenic nomas . The deactivation of vitamin- amines is in fact a general process- ity as some plants containing these B by gyromitrin elicits a decrease- touching other aldehydes as betaine- compounds are consumed and/or- of GABA synthesis, causing convul aldehyde, and they react with ethan contaminate crops. The carcinogenic sions. At lower doses, metabolic ef 6 loss, olamine and form lipofuscin precipi mechanism for pyrrolizidine alka fect of hyperglycemias followed by tates in macular degenerative disease- loids may depend on vitamin B - hypoglycaemia indicate an alteration- or Alzheimer’s disease. In case of following the formation of adducts of pancreatic controls. In agreement 6 pyridoxal-adduct reactions, the re as observed for pyrroluria. Howev with the hypothesis discussed, a de 6 - sulting B deficiency affects enzymes er, this remains to be proven in this crease of pancreatic GABA caused such as GAD, which require B ; as a re particular case. One even wonders if cancer in these animal experiments.- sult, the synthesis of GABA decreases;- the same mechanism would not be- The carcinogenicity of gyromitra in transaminases and other enzymes valid for nicotine carcinogenicity; a humans has not been observed; boil are also perturbed. In general, neu- catabolic derivative of the pyrroli ing probably decreases the level of rological consequences predominate, dine ring of nicotine may be oxidized hydrazines in gyromitra mushrooms. 6 - convulsions and schizophrenic dis into a pyrroline, which would then These mushrooms are consumed in 6 - orders. However, it is possible that a bind vitamin B and affect pancre Finland, northern Europe and North chronic B deficiency may also affect atic GABA, leading to cancer. Alterna- America; they should however be- enzymes in the periphery, leading2+ to tively, nicotine, a known cholinergic considered dangerous, particularly - 6 poor GABA synthesis in the pancreas. agonist, may also act as a GABA an if residual gyromitrin causes a grad 6 Moreover, a parallel loss of Zn , ex tagonist. The deactivation of vitamin ual deactivation of vitamin B and creted Licenseewith the complex, OA Publishing impairs the London B by 2013. pyrroles Creative differs from Commons the Schiff Attributiona pancreatic License GABA (CC-BY) failure, leading

Israël M. for betel nut consumers and for diets de-activating vitamin B6

- - to cancer, as observed in the animal It is certainly difficult to explain, ‘cross-talk’29 with tyrosine kinase re Carcinogenicmodels. effects associated at the mechanistic level, the carcino ceptors and boost the MAPK route with beta cell GABA deficiency genic effect resulting from a failure- of target cells. - - of cellular interactions mediated There is however an apparent by GABA. However, it is quite prob contradiction, because some stud Normally, insulin and growth fac able that this pancreatic deficiency ies indicate that the direct action of tors activate the mitogen-activated- boosts the MAPK mitogenic route- GABA on some29 cells favours their protein kinase (MAPK) mitogenic (the target of most oncogenes) and proliferation . This takes place, for- route and the PI3 kinase-PKB path provokes cancer as for other onco example, in immature neurons– with way via tyrosine kinase receptors.- genes. We know, for instance, that an elevated intracellular Cl concen The latter will act on ‘switch board’- GABA inhibits adrenal medulla cells.- tration; in such cells, the – action of kinases and phosphatases, control Thus, a decrease of GABA synthesis- GABA elicits an efflux of Cl by GABA2+ ling enzymes supporting anabo or release increases epinephrine re A receptors, thereby depolarizing lism. In parallel, beta cells turn off lease. Epinephrine inhibits pancre- them. The depolarization opens Ca alpha cells releasing glucagon with atic delta cells and does the job for- channels and calcium activates RAS GABA; G protein-coupled receptors- GABA, which is deficient. Thus, epi and the MAPK pathway, eliciting cell (GPCRs) and PKAs are switched off, nephrine decreases somatostatin re proliferation. In this case, a decrease- while enzymes supporting catabo lease from delta cells and increases3 in GABA levels would then inhibit lism are silenced. Hence, if GABA is the actions of growth hormone and- cell proliferation. However, the situa not released, glucagon is liberated in- Insulin like growth factor (IGF) . We tion is completely different for many parallel to insulin, leading to a mixed know that IGF activates the tyros- more cells that are hyperpolarized hybrid anabolism–catabolism reac- ine kinase receptors and boosts the by GABA. In alpha cells, for example, tion, which is typical of cancer. In the action of insulin, triggering the mi- a decrease in GABA levels elicits a present work, we evaluated the pan- togenic MAPK pathway. Moreover,- relative depolarization, increasing creatic hypothesis, considering that- beta cells are known to release cho intracellular calcium, which triggers deficient cellular interactions medi line derivatives controlling methyla the release of glucagon in response ated by GABA cause cancer. Epide tion processes; the methylation of to hypoglycaemia. In other target 6-related miological works and experimental a phosphatase PP2A targets it over cells where GABA has a similar hyper observations on vitamin B - the signalling kinases, where it acts polarizing effect, an arrest of GABA GABA deficiencies seem to confirm as a brake, limiting the mitogenic elicits their depolarization, and a this view. It was advanced essen signal. We have earlier27,28 indicated calcium increase, which activates tially because it explained the27,28 hybrid that a poor PP2A methylation boosts RAS and boosts the MAPK pathway, cancer metabolism, giving mitotic- the MAPK pathway . If beta cells which triggers their proliferation cells a selective advantage . In release insulin without the partner (Figure 2). fact, this hypothesis deals with defi compounds regulating its effect, Inevitable mutations will select the cient cellular interactions mediated the2+ process may be carcinogenic most aggressive mitotic cells; each by GABA; it2+ also takes into account the GABA is fundamental; however, daughter cell inherits tyrosine kinase the fact that other insulin partners Zn and choline derivatives are also- receptors and a mitotic capability; an such as Zn or choline derivatives essential as previously discussed.- increase of the IGF/IGFBP ratio plays may also fail. These insulin partners- In addition, epigenetic changes in a critical a role28 in this symmetrical are normally released for controlling duced by the hybrid metabolic situ mitosis, geometrically increasing the neighbouring cells; they also regu ation decrease the expression of Conclusiontumour mass . late the strength of insulin signals. many genes. A decrease27,28 in IGFBP (an The hypothesis is not contradicted- IGF binding protein), will no longer- if GABA has positive effects on cell limit the action of IGF . The MAPK- Food agencies and epidemiological proliferation; this is a parallel ques mitogenic route is not only stimulat studies have warned consumers of- tion that deserves discussion. The ed but is also out of control, as it oc the dangers of betel nuts, tobacco,- action of GABA on cell proliferation curs for other oncogenes, explaining pyrrolizidine alkaloids or mycotox has been reviewed in Ref. No. 29.- the carcinogenicity resulting from ins and gyromitrin. It is however dif- The interpretation of these results- a pancreatic beta cell deficiency. It ficult to avoid all potential risks; even- is compatible with our daring pan is not insulin but its other beta cell- some type of honeys contain pyr creatic hypothesis,3 situating the pri partners that fail. rolizidines, when bees pollinize flow mary cause of cancer in endocrine We also point that GPCRs acti ers containing this alkaloid. Many pancreasLicensee. OA Publishing Londonvated 2013. by the Creative epinephrine Commons increase Attributioncomestible License mushrooms (CC-BY) also contain

Israël M. for betel nut consumers and for diets de-activating vitamin B6

Critical review

hydrazine alkaloids. Consuming betel nuts is a tradition touchingG. esculenta millions is of people in Asia, and it is difficult to change cultural habits. consumed in northern countries, and cooking, probably, neutralizes the toxin. We are aware that betel nuts impair GABA release and uptake. We 6 - have identified at least three types of vitamin B deactivations (amines hy 6 is the drazines and pyrroles) that decrease- GABA synthesis, as vitamin B - cofactor of the GABA synthetizing en zymes. In all cases, the risk for can cer was clear or probable. A chronic inhibition of GABA receptors should- also be carcinogenic, as observed for- fipronil, a phenyl pyrazole insecti cide that inhibits30 GABA-gated chlo ride channels . When fipronil was- administered to rats in their diet, for nearly 2 years, an increased inci dence of thyroid gland tumours was observed. The carcinogenicity for humans has not31 been observed, but the risk is considered as indicated by official agencies . - Figure 2: Pancreatic GABA failure and proliferation. It is perhaps useful to understand carcinogenic mechanisms to neu Decrease of GABA 6 6 tralize them and to add protective release from pancreatic beta cells has multiple causes, some of which compounds to the diet—vitamin B result from vitamin B deactivation; the decrease of GABA has several or nutrients containing GABA—and consequences. First, adrenal medulla cells are no longer inhibited by avoid diets that are limited to a single 1 GABA and release epinephrine, which inhibits delta cells and the release of nutrient. Even rice is responsible for a somatostatin. Epinephrine does the job for GABA. Decrease of somatostatin severe vitamin B deficiency, Beriberi, enhances growth hormone release, and therefore IGF, which cooperates when it is decorticated because the with insulin, and strongly stimulates the tyrosine kinase receptor. The vitamin is present in the husk. Maize MAPK pathway is boosted; in parallel, PI3 kinase-PKB supports anabolism. (transgenic or wild-type) is certainly 3 6 - Activation of the MAPK pathway induces2+ proliferation, particularly if its dangerous when it is in the major normal control brakes (methylated PP2A or IGFBP) are not activated. The diet; vitamin B and B deficiencies re beta cell deficiency touches GABA, Zn and choline derivatives, possibly sult from intrinsic properties of maize- affecting PP2A methylation. Second, GABA is spilled – over alpha and2+ other metabolism, and in the past, native cells; they are at rest, hyperpolarized by the influx of Cl by GABA A receptors. cultivators reduced the danger asso Now, if GABA decreases, relative depolarization takes place and Ca entry ciated with maize by nixtamalization.- elicits2+ the release of glucagon from alpha cells; in other cells with similar As for the hypothesis, considering- GABA A receptors, depolarization following the arrest of GABA increases that cancer is caused by deficient cel Ca and activates directly RAS, which boosts the MAPK oncogenic pathway lular interactions in endocrine pan even more. Third, we have seen that GABA failure elicits epinephrine release, creas, resulting essentially from GABA- which may activate GPCRs, inducing a transactivation of the tyrosine kinase failure, a ‘grandeur nature’ validation receptor-MAPK pathway in the cells. Moreover, GPCR of the G type activates is unfortunately observed in popula- adenylate cyclase cAMP and PKA, supporting the catabolic part of this tions regularly consuming betel nuts, hybrid metabolism. The MAPK pathway is not only boosted but is also out which affect pancreatic GABA and in of control, explaining the carcinogenicity resulting from this pancreatic beta crease the risk for cancer. There are cell failure. many nutritional conditions that affect Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

Israël M. for betel nut consumers and for diets de-activating vitamin B6

Critical review

- Areca catechu the pancreatic system such as inad ( ) on liver cirrhosis and 17. Séralini GE, Clair E, Mesnage R, Gress 6 equate maize diets poor in niacin and hepatocellular carcinoma: a population S, Malatesta N, Hennequin D, et al. Long vitamin B and drugs or endogenous study from an area with a high prevalence term toxicity of a Roundup herbicide and 6 of hepatitis B and C infections. Public a Roundup-tolerant genetically modified metabolites that decrease vitamin - - health Nutr. 2009 Jan;12(1):129–35. maize. 2012 http://dxdoi. org/10.1016/ B and pancreatic GABA. Gyromitrin 6. Choudhury Y, Sharan RN. Ultrastruc j.fct.2012; 08.005. poisoning, for example, has been re tural alterations in liver of mice exposed 18. Do Carmo Langiano V, MartinezProchil CBR.- sponsible for causing cancer in animal chronically and transgenerationally to- odusToxicity lineatus and effects of a glyphosate-based experiments. An excess of amines and aqueous extract of betel nut. Implications herbicide on the Neotropical fish pyrroles are also dangerous. Blockade- in betel nut-induced carcinogenesis. Mi . Comp Biochem Physiol of GABA receptors is also a risk. Most crosc Res Tech. 2010 May; 73(5):530–9. C Toxicol Pharmacol. 2008 Mar;147:- of the nutritional conditions exam- 7. Andersson HC, Arpaia S, Bartsch D, 222–31. ined that disrupted this pancreatic Casacuberta J, Davies H, Du Jardin P, et 19. Jackson JA, Riordan HD, Neath al. Herbicide tolerant GM maize NK603 ery S, Riordan NH. Urinary pyrrole in theGABAergic hypothesis control3,32 system were asso for cultivation, food and feed uses and health and disease. J Orthomol Med. ciated with cancer, in agreement suppressed with - 1 import processing and for the renewal 1997;12(2):96–8. . Niacin suppressed of the authorisation of existing products. 20. Roszmann GM. Analysis of pyr pellagra and vitamin B 6 EFSA J. 2009;1137:15–50. - rolizidine alkaloids in Crotalaria species Beriberi. We hope that controlling 8. Querci M, Mazzara M. Analyse- by HPLC6MS/MS in order to evaluate vitamin B and GAD will decrease the d’échantillons alimentaires pour la pres related food health risks. PhD thesis Acknowledgementsrisk for cancer. ence d’organismes génétiquement modi Pretoria University, Paraclinical science. fiés Module 7 caractéristiques du soja 2007 - Roundup Ready, du maïs MON810 et du 21. Lamé MW, Jones AD, Morin D, Segall- I am grateful to Dr Alan Storey for a maïs Bt-176. JRC European commission, HJ, Wilson DW. Biliary excretion of pyr Abbreviationsvaluable discussion list on the subject. 1–20. rolic metabolites of (14C) monocrota 9. Agrobacterium tumefaciens http:// line in rat. Drug Metab Dispos. 1995- fr.wikipedia.org/wiki/Agrobacterium Mar;23(3):422–9.

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Israël M. for betel nut consumers and for diets de-activating vitamin B6