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Toxicology expert raises alarm over potential neurotoxins in graviola/soursop

4 commentsBy Elaine Watson , 10-May-2012
Last updated on 10-May-2012 at 20:42 GMT

Schauss: A. muricata (graviola/soursop) contains 'potential neurotoxins' (picture: Damien Boilley)
Schauss: A. muricata (graviola/soursop) contains 'potential neurotoxins' (picture: Damien Boilley)

A toxicology expert says he is shocked to see firms in the supplements trade developing products containing extracts from the tropical fruit graviola (also known as soursop or Annona muricata) given its association with atypical Parkinson's disease.

Dr Alex Schauss is senior research director at AIBMR Life Sciences, which specializes in toxicological/safety testing, nutraceutical research, managing clinical trials, and regulatory compliance.

He contacted NutraIngredients-USA after seeing new ads for dietary supplements containing extracts from the fruit and leaves of graviola, which, he says, contain a neurotoxin called annonacin.

Epidemiological, in vitro and animal data all indicate that chronic consumption could be risky, he said.

“I did nutrition research in Guam in the early 1980s on behalf of a legislative committee on the island over a span of three years and we found an association between chronic fruit consumption and atypical Parkinson's disease [that was] shocking. 67% of Parkinson's cases were of the atypical form, compared to less than 5% in Europe.”

‘I was somewhat shocked given what I knew of its neurotoxicity’

He added: “What worries me is the appearance of the fruit in products of late given that it contains isoquinoline alkaloids that have been linked to the development of atypical Parkinson's.”

The recent interest in graviola appeared to be on the back of research suggesting it has anti-cancer properties, he said.  

“I received inquiries on these [anti-cancer] claims… I was somewhat shocked given what I knew of its neurotoxicity when one caller mentioned that they were considering bringing it out as a juice.”

Why is this not better known in the supplements trade?

He added: “I spoke at a recent international symposium on the safety of natural products and mentioned soursop. Quite a number of scientists in the audience came from tropical/sub-tropical countries and recognized the fruit immediately when shown on a slide, but did not know about the associated neurotoxic compounds it contains.

“During lunch, one of the attendees did a PubMed search and confirmed my comments earlier that morning and asked why this was not better known.”

Concerns about graviola were first raised several years ago, said Schauss. “But people forget. So when given the opportunity to co-author with Professor Badrie [a professor at the University of the West Indies] on the subject [in 2009] we agreed that recapping the toxicology of the fruit was important.”

A. muricata and other plants of Annonaceae contain potential neurotoxins

In chapter 39 of the book Bioactive Foods in Promoting Health edited by Ronald Ross Watson and Victor R. Preedy (Oxford: Academic Press, 2009) Schauss and Badrie write:

The aqueous extract of leaves and the extract of the root bark of Annona muricata and infusions and decoctions of the fruit have been shown in both in vitro and in vivo experiments to be a potentially toxic inhibitor of the mitochondrial respiratory chain.

“Experimental studies have confirmed annonacin, an isoquinoline derivative, the major acetogenin found in soursop, as the toxic agent responsible for this effect. A. muricata and other plants of Annonaceae contain potential neurotoxins, particularly the isoquinolinic alkaloids and acetogenins, structurally homogenous fatty acid derivatives known as polyketides specific to Annonaceae.

“This class of polyketides are among the most potent inhibitors of complex I of the mitochondrial respiratory chain known in nature, some 50-fold more potent than the class complex I inhibitor MPP + and two times more potent than rotenone in inducing neuronal death.”

Epidemiological evidence

The significance of these findings relates to the abnormally high rate of atypical parkinsonism found on islands such as Guam in the Northern Mariana islands, New Caledonia, western New Guinea, the Kii peninsula of Japan, and the French West Indian island of Guadeloupe in the Caribbean, where epidemiological evidence “suggests a close association of the disease with regular consumption of soursop fruit, infusions, and decoctions”, they observe.

“What is interesting is the virtual disappearance over the years of the disproportionate incidence of atypical parkinsonism previously reported in Guam and New Guinea.

“It has been suggested that the significant reduction in incidences may be due to changes in diet in New Guinea and in Guam, in particular owing to the adoption of Western diets and the abandonment of native foods, such as soursop.”

Fruit and leaves represent potential risk

Conerns have been raised about the leaf as well as the fruit, he added, citing papers by Champy et al (click here , here and here ). A phenomenologic study of parkinsonism by Caparros-Lefebvre in The Lancet also raises concerns about herbal teas, he added. Click here .

NutraIngredients-USA has contacted several firms selling graviola supplements for comment including Raintree Nutrition , Swanson  and Vitabase but has not had any feedback to date.

However, NOW Foods technical director Dr Michael Lelah said: "NOW Foods is aware of the potential safety concerns about graviola. We use a leaf extract which contains annonacin levels many times lower than the safe level. 

"Additionally, no adverse events have been reported for our product. On the other hand, high concentrations of annonacin are found in the fruits or seeds, which are consumed by Caribbean populations."

American Botanical Council (ABC) founder Mark Blumenthal was unavailable for comment.

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4 comments (Comments are now closed)

Graviola (soursop)

Toxicity of Annonaceae for dopaminergic neurons: Potential role in atypical parkinsonism in Guadeloupe
Annie Lannuzel, MD, PhD 1 *, Patrick P. Michel, PharmD, PhD 2, Dominique Caparros-Lefebvre, MD, PhD 1, Jacqueline Abaul, PhD 3, Reynald Hocquemiller, PharmD, PhD 4, Merle Ruberg, PhD 2
1Service de Neurologie, Centre hospitalier universitaire des Antilles et de la Guyane, Pointe-à-Pitre, Guadeloupe, France
2INSERM 289, Hôpital de la Salpêtrière, Paris, France
3Laboratoire COVACHIM, UFR des Sciences Exactes et Naturelles, Université des Antilles et de la Guyane, Pointe-à-Pitre, Guadeloupe; France
4Laboratoire de Pharmacognosie, UPRES-A 8076 CNRS, Faculté de Pharmacie, Châtenay-Malabry; France
email: Annie Lannuzel (lannuzel@ais.gp)

*Correspondence to Annie Lannuzel, Service de Neurologie, CHU des Antilles et de la Guyane, Pointe-à-Pitre, 97159 Abymes, Guadeloupe, France

Keywords
movement disorders parkinsonism neurotoxicology apoptosis

Abstract
In the French West Indies there is an abnormally high frequency of levodopa-resistant parkinsonism, suggested to be caused by consumption of fruit and infusions of tropical plants, especially Annona muricata (corossol, soursop). To determine whether toxic substances from this plant can cause the neuronal degeneration or dysfunction underlying the syndrome, we exposed mesencephalic dopaminergic neurons in culture to the total extract (totum) of alkaloids from Annona muricata root bark and to two of the most abundant subfractions, coreximine and reticuline. After 24 hours, 50% of dopaminergic neurons degenerated with 18 g/ml totum, 4.3 g/ml (13 M) coreximine, or 100 g/ml (304 M) reticuline. The effects of the alkaloid totum were not restricted to the population of dopaminergic cells since GABAergic neurons were also affected by the treatment. Nuclei in dying neurons showed DNA condensation or fragmentation, suggesting that neuronal death occurred by apoptosis. Cell death was not excitotoxic and did not require toxin uptake by the dopamine transporter. Neurodegeneration was attenuated by increasing the concentration of glucose in the culture medium, which also reduced the effect of the dopaminergic neurotoxin MPP+, a mitochondrial respiratory chain inhibitor. Toxin withdrawal after short-term exposure arrested cell death. Acute treatment with totum, coreximine, or reticuline reversibly inhibited dopamine uptake by a mechanism that was distinct from that causing neuronal death. GABA uptake was not reduced under the same conditions. This study suggests that alkaloids from A. muricata can modulate the function and the survival of dopaminergic nerve cells in vitro. It is therefore conceivable that repeated consumption could cause the neuronal dysfunction and degeneration underlying the West Indian parkinsonian syndrome. © 2002 Movement Disorder Society.

The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.
Neuroscience. 2003;121(2):287-96.
The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata ( graviola ), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. The uptake of [(3)H]-dopamine used as an index of dopaminergic cell function was similarly reduced. Toxic effects were seen at lower concentrations when the incubation time was extended by several days whereas withdrawal of the toxin after a short-term exposure (<6 h) arrested cell demise. Unlike MPP(+) but similar to rotenone, the acetogenin also reduced the survival of non-dopaminergic neurons. Neuronal cell death was not excitotoxic and occurred independently of free radical production. Raising the concentrations of either glucose or mannose in the presence of annonacin restored to a large extent intracellular ATP synthesis and prevented neuronal cell demise. Deoxyglucose reversed the effects of both glucose and mannose. Other hexoses such as galactose and fructose were not protective. Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.

Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.
J Neurochem. 2004 Jan;88(1):63-9.
In Guadeloupe, epidemiological data have linked atypical parkinsonism with fruit and herbal teas from plants of the Annonaceae family, particularly Annona muricata ( graviola ). These plants contain a class of powerful, lipophilic complex I inhibitors, the annonaceous acetogenins. To determine the neurotoxic potential of these substances, we administered annonacin, the major acetogenin of graviola, to rats intravenously with Azlet osmotic minipumps (3.8 and 7.6 mg per kg per day for 28 days). Annonacin inhibited complex I in brain homogenates in a concentration-dependent manner, and, when administered systemically, entered the brain parenchyma, where it was detected by matrix-associated laser desorption ionization-time of flight mass spectrometry, and decreased brain ATP levels by 44%. In the absence of evident systemic toxicity, we observed neuropathological abnormalities in the basal ganglia and brainstem nuclei. Stereological cell counts showed significant loss of dopaminergic neurones in the substantia nigra (-31.7%), and cholinergic (-37.9%) and dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic neurones (-39.3%) in the striatum, accompanied by a significant increase in the number of astrocytes (35.4%) and microglial cells (73.4%). The distribution of the lesions was similar to that in patients with atypical parkinsonism. These data are compatible with the theory that annonaceous acetogenins, such as annonacin, might be implicated in the aetiology of Guadeloupean parkinsonism and support the hypothesis that some forms of parkinsonism might be induced by environmental toxins.

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Posted by AZ
01 August 2012 | 01h08

Food chemistry analysis on annonacae family

Has there been any food chemistry HPLC or mass spec data comparing the quantity of annonacin and other neurotoxins to compare and gauge potential neurtoxic compounds?
Infact these compounds could exist in such small quantity in some members of the family that it may not be significant.

I looked on Pubmed and could not find any of this data. What is known in terms of quantity and potential in vitro testing.
I mean we could go crazy over all this without really talking numbers. Apples have seeds containing cyanide but that hasnt seemed to keep us from that old analogy "an apple a day......."

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Posted by J
14 May 2012 | 18h22

Phytochemical toxins

Carrots also have a neurotoxin but if we eat them in moderation they cause no harm due the synergy of chemical co-factors that negate the poison's effect. It is only when the neurotoxin is extracted from these other compounds that it becomes poisonous. Its interesting that supplements are a concern for the health care industry, but the fact manufacturers have been adding the neurotoxin sodium Lauryl Sulfate to our shampoo for years has not caused doctors to jump on the soapbox appalled about this practice. Its hard to believe there is anyone still gullible enough to believe that professionals working in sickness care actually want them to remain healthy, when health is contrary to the professionals economic survival.

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Posted by Clara Thomas
14 May 2012 | 16h18

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