Amygdalin

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Amygdalin
Amygdalin structure.svg
Amygdalin-from-xtal-3D-balls.png
Identifiers
CAS number 29883-15-6 N
PubChem 34751
ChemSpider 570897 YesY
UNII 214UUQ9N0H YesY
MeSH Amygdalin
ChEBI CHEBI:17019 YesY
ChEMBL CHEMBL461727 YesY
Jmol-3D images Image 1
Image 2
Properties
Molecular formula C20H27NO11
Molar mass 457.43 g mol−1
Hazards
NFPA 704
Flammability code 0: Will not burn. E.g., water Health code 1: Exposure would cause irritation but only minor residual injury. E.g., turpentine Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
Related compounds
Related compounds vicianin, laetrile
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Amygdalin (from Ancient Greek: ἀμυγδαλή amygdálē "almond"), C20H27NO11, is a glycoside initially isolated from the seeds of the tree Prunus dulcis, also known as bitter almonds, by Pierre-Jean Robiquet and Antoine Boutron-Charlard, in 1830[1] and subsequently investigated by Liebig and Wöhler in 1830. Several other related species in the genus of Prunus, including apricot (Prunus armeniaca) and black cherry (Prunus serotina),[2] contain amygdalin. Amygdalin is also found in apples.[3]

Since the early 1950s, both amygdalin and a modified form named laetrile or Vitamin B17 have been promoted as cancer cures. However, neither of these compounds nor any other derivatives are vitamins in any sense,[4] and studies have found them to be clinically ineffective in the treatment of cancer, as well as dangerously toxic. They are potentially lethal when taken by mouth, because certain enzymes (in particular, glucosidases that occur in the gut and in various kinds of seeds, edible or inedible) act on them to produce cyanide.[5][6][7][8][9] The promotion of laetrile to treat cancer has been described in the medical literature as a canonical example of quackery,[10][11][12] and as "the slickest, most sophisticated, and certainly the most remunerative cancer quack promotion in medical history."[4]

Chemistry[edit]

Amygdalin is extracted from almonds or apricot kernels by boiling in ethanol; on evaporation of the solution and the addition of diethyl ether, amygdalin is precipitated as white minute crystals. Liebig and Wöhler were already able to find three decomposition products of the newly discovered amygdalin: sugar, benzaldehyde, and prussic acid (hydrogen cyanide).[13] Later research showed that sulfuric acid decomposes it into D-glucose, benzaldehyde, and prussic acid; while hydrochloric acid gives mandelic acid, D-glucose, and ammonia.[14]

Several glucosidase enzymes are known to act on amygdalin, leading to its decomposition by various pathways. Maltase causes partial degradation, giving D-glucose and mandelic nitrile glucoside, C6H5CH(CN)O·C6H11O5. Emulsin, on the other hand, decomposes it into benzaldehyde, cyanide, and two molecules of glucose; this enzyme occurs in the bitter almond, and consequently the seeds invariably contain free cyanide and benzaldehyde. An "amorphous amygdalin" is said to occur in the cherry laurel (Prunus laurocerasus). Lastly, amygdalin beta-glucosidase and prunasin beta-glucosidase consecutively catalyze loss of the two glucose units to yield mandelonitrile, which can then decompose to form free cyanide and benzaldehyde. One gram of amygdalin would release 68 mg of hydrogen cyanide if fully decomposed along this route.

Natural amygdalin has the R configuration at the chiral benzyl center. Under mild basic conditions, this stereogenic center epimerizes; the S epimer is called neoamygdalin.[15]

Laetrile[edit]

Laetrile (CAS No. 1332-94-1)

Amygdalin is sometimes confused with laevomandelonitrile, also called laetrile for short; however, amygdalin and laetrile are different chemical compounds.[15] Laetrile, which was patented in the United States, is a semi-synthetic molecule sharing part of the amygdalin structure, while the "laetrile" made in Mexico is usually amygdalin, the natural product obtained from crushed apricot pits, or neoamygdalin.[16]

Laetrile has a melting point of 214 to 216 degrees Celsius.[17] Its Chemical Abstracts Service Registry Number is 1332-94-1 and its International Union of Pure and Applied Chemistry nomenclature name is (2S,3S,4S,5R,6R)-6-[(R)-cyano(phenyl)methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid. Laetrile's chemical formula is C14H15NO7 and its PubChem number is 5484354.[18] Its molecular weight is 309.2714 grams/mole.[18] Laetrile is also classified as a cyanogenic glycoside.[19]

Though it is sometimes sold as "Vitamin B17", it is not a vitamin. Amygdalin/laetrile was claimed to be a vitamin by chemist Ernst T. Krebs in the hope that if classified as a nutritional supplement it would escape the federal legislation regarding the marketing of drugs. He could also capitalise on the public fad for vitamins at that time.[4]

Toxicity[edit]

The metabolism of amygdalin produces hydrogen cyanide, a potent toxin. Beta-glucosidase, one of the enzymes that catalyzes the release of cyanide from amygdalin, is present in the human small intestine and in a variety of common foods. This leads to an unpredictable and potentially lethal toxicity when amygdalin or laetrile is taken orally.[4][20][21] Ingestion of purified amygdalin or apricot kernels can cause severe toxicity and death due to cyanide poisoning.[16] Numerous case reports in medical literature describe serious cyanide poisoning in patients who ingested laetrile as a cancer treatment.[10][22] Blood cyanide concentrations may be measured as a means of confirming the diagnosis in hospitalized patients or to assist in the forensic investigation of a fatal overdose.[23]

Some laetrile promoters have claimed that the cyanide generated by laetrile is immediately harmlessly detoxified by the mitochondrial enzyme rhodanese into thiocyanate. However, these claims are false. First, because thiocyanate is also toxic, although to a lesser degree. Second, the body only can use the small amount of rhodanese that is present in the blood, regardless of the stores present in kidneys and liver. Third, the limited factor in this conversion are the stores of cystine, cysteine, and other sulfur compounds, which are rapidly depleted in laetrile poisoning. Fourth, blood analysis shows undetoxified cyanide in persons poisoned with laetrile or with apricot kernels.[10]

Cancer treatment[edit]

Amygdalin was first isolated in 1830. In 1845 it was used as a cancer treatment in Russia, and in the 1920s in the United States, but it was considered too poisonous.[24] In the 1950s, a purportedly non-toxic, synthetic form was patented for use as a meat preservative,[25] and later marketed as laetrile for cancer treatment.[24]

The U.S. Food and Drug Administration prohibited the interstate shipment of amygdalin and laetrile in 1977.[26][27] Thereafter, 27 U.S. states legalized the use of amygdalin within those states.[28]

Initial studies at Sloan-Kettering[edit]

In 1972, Memorial Sloan-Kettering Cancer Center (MSKCC) board member Benno C. Schmidt, Sr. convinced the hospital to test laetrile so that he could assure others of its ineffectiveness "with some conviction."[29] Kanematsu Sugiura, the scientist who performed the requested tests, found that laetrile inhibited secondary tumors in mice, though it did not destroy the primary tumors. He repeated the experiment several times with the same results. However, three other researchers were unable to confirm Sugiura's results. While these uncontrolled and inconclusive results were considered too preliminary to publish, they were leaked to laetrile advocates, resulting in significant public attention.[29]

To expand on Sugiura's results, MSKCC researchers conducted a controlled experiment in which they injected some mice with laetrile (as Sugiura had done) and others with placebo. Sugiura, who was unaware of which mice had received laetrile, performed the pathologic analysis. In this controlled, blinded follow-up of Sugiura's initial uncontrolled experiment, laetrile showed no more activity than placebo.[29]

Subsequently, laetrile was tested on 14 tumor systems without evidence of effectiveness. Given this collection of results, MSKCC concluded that "laetrile showed no beneficial effects."[29] Mistakes in the MSKCC press release were highlighted by a group of laetrile proponents led by Ralph Moss, former public affairs official of MSKCC who was fired following his appearance at a press conference accusing the hospital of covering up the benefits of laetrile.[30] These mistakes were considered scientifically inconsequential, but Nicholas Wade in Science stated that "even the appearance of a departure from strict objectivity is unfortunate."[29] The results from these studies were published all together.[31]

Subsequent clinical studies[edit]

A 2011 systematic review from the Cochrane Collaboration found:

The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk–benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative.[32]

The authors also recommended, on ethical grounds, that no further clinical research into laetrile or amygdalin be conducted.[32]

Given the lack of evidence, laetrile has not been approved by the U.S. Food and Drug Administration.[16]

The U.S. National Institutes of Health evaluated the evidence separately and concluded that clinical trials of amygdalin showed little or no effect against cancer.[24] For example, a 1982 trial of 175 patients found that tumor size had increased in all but one patient.[33] The authors reported that "the hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range."[8]

The study concluded "Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment".

Advocacy and legality[edit]

Laetrile was proven clinically ineffective more than 30 years ago and is considered a canonical example of "quackery".[4] Nonetheless, advocates for laetrile dispute this label, asserting that there is a conspiracy between the U.S. Food and Drug Administration, the pharmaceutical industry and the medical community, including the American Medical Association and the American Cancer Society, to exploit the American people, and especially cancer patients. Advocates of the use of laetrile have also changed the rationale for its use, first as a treatment of cancer, then as a vitamin, then as part of a "holistic" nutritional regimen, or as treatment for cancer pain, among others, none of which have any significant evidence supporting its use. Despite the lack of evidence for its use, laetrile developed a significant following due to its wide promotion as a "pain-free" treatment of cancer as an alternative to surgery and chemotherapy that have significant side effects. The use of laetrile in place of known effective treatments of cancer led to a number of deaths.[34]

The FDA and AMA crackdown, begun in the 1970s, effectively escalated prices on the black market, played into the conspiracy narrative and helped unscrupulous profiteers foster multi-million dollar smuggling empires.[35][36][37]

Some North American cancer patients have traveled to Mexico for treatment with the substance, allegedly under the auspices of Ernesto Contreras.[38] The actor Steve McQueen died in Mexico following cancer treatment with laetrile and surgery to remove a stomach tumor while undergoing treatment for peritoneal mesothelioma (a cancer that attacks the lining of the abdomen) under the care of William D. Kelley, a dentist and orthodontist who devised a supposed cancer treatment based on laetrile.[39]

Laetrile advocates in the United States include Dean Burk (now deceased), a former chief chemist of the National Cancer Institute cytochemistry laboratory,[40] and national arm wrestling champion Jason Vale, who claimed that his kidney and pancreatic cancers were cured by eating apricot seeds. Vale was convicted in 2003 for, among other things, marketing laetrile.[41] The court also found that Vale, who had made at least $500,000 from his illegal sales of laetrile, had fraudulently marketed the substance.[42]

The US Food and Drug Administration continues to seek jail sentences for vendors marketing laetrile for cancer treatment, calling it a "highly toxic product that has not shown any effect on treating cancer."[43]

See also[edit]

Notes[edit]

  1. ^ "A chronology of significant historical developments in the biological sciences". Botany Online Internet Hypertextbook. University of Hamburg, Department of Biology. 2002-08-18. Archived from the original on 20 August 2007. Retrieved 2007-08-06. 
  2. ^ Swain E, Poulton JE (October 1994). "Utilization of Amygdalin during Seedling Development of Prunus serotina". Plant physiology 106 (2): 437–445. doi:10.1104/pp.106.2.437. PMC 159548. PMID 12232341. 
  3. ^ Islamiyat F. Bolarinwaa, Caroline Orfila, Michael R.A. Morgan (June 2014). "Amygdalin content of seeds, kernels and food products commercially-available in the UK". Food Chemistry 152: 133–139. doi:10.1016/j.foodchem.2013.11.002. 
  4. ^ a b c d e Lerner IJ (1981). "Laetrile: a lesson in cancer quackery". CA Cancer J Clin 31 (2): 91–5. doi:10.3322/canjclin.31.2.91. PMID 6781723. 
  5. ^ Moss, M. ; Khalil, N. ; Gray, J. "Deliberate self-poisoning with Laetrile" CMA JOURNAL/NOVEMBER 15, 1981/VOL. 125 pp. 1126–1127
  6. ^ Ellison NM, Byar DP, Newell GR (September 1978). "Special report on Laetrile: the NCI Laetrile Review. Results of the National Cancer Institute's retrospective Laetrile analysis". N. Engl. J. Med. 299 (10): 549–52. doi:10.1056/NEJM197809072991013. PMID 683212. 
  7. ^ Moertel CG, Ames MM, Kovach JS, Moyer TP, Rubin JR, Tinker JH (February 1981). "A pharmacologic and toxicological study of amygdalin". JAMA 245 (6): 591–4. doi:10.1001/jama.1981.03310310033018. PMID 7005480. 
  8. ^ a b Moertel CG, Fleming TR, Rubin J (January 1982). "A clinical trial of amygdalin (Laetrile) in the treatment of human cancer". N. Engl. J. Med. 306 (4): 201–6. doi:10.1007/s00520-006-0168-9. PMID 7033783. 
  9. ^ O'Brien B, Quigg C, Leong T (October 2005). "Severe cyanide toxicity from 'vitamin supplements'". Eur J Emerg Med 12 (5): 257–8. doi:10.1097/00063110-200510000-00014. PMID 16175068. 
  10. ^ a b c Herbert V (May 1979). "Laetrile: the cult of cyanide. Promoting poison for profit". Am. J. Clin. Nutr. 32 (5): 1121–58. PMID 219680. 
  11. ^ Lerner IJ (February 1984). "The whys of cancer quackery". Cancer 53 (3 Suppl): 815–9. doi:10.1002/1097-0142(19840201)53:3+<815::AID-CNCR2820531334>3.0.CO;2-U. PMID 6362828. 
  12. ^ Nightingale SL (1984). "Laetrile: the regulatory challenge of an unproven remedy". Public Health Rep 99 (4): 333–8. PMC 1424606. PMID 6431478. 
  13. ^ F. Wöhler, J. Liebig (1837). "Ueber die Bildung des Bittermandelöls". Annalen der Pharmacie 22 (1): 1–24. doi:10.1002/jlac.18370220102. 
  14. ^ J. W. Walker, V. K. Krieble (1909). "The hydrolysis of amygdalin by acids. Part I". Journal of the Chemical Society 95 (11): 1369–77. doi:10.1039/CT9099501369. 
  15. ^ a b Fenselau C, Pallante S, Batzinger RP (November 1977). "Mandelonitrile beta-glucuronide: synthesis and characterization". Science 198 (4317): 625–7. doi:10.1126/science.335509. PMID 335509. 
  16. ^ a b c What is laetrile?, National Cancer Institute, Retrieved on 14 January 2007
  17. ^ Collins, Peter M. (2005). Dictionary of Carbohydrates. Boca Raton: CRC Press. p. 678. ISBN 0-8493-3829-8. 
  18. ^ a b Laetrile data in PubChem.
  19. ^ Hoffman, E. J. (1999). Cancer and the search for selective biochemical inhibitors. Boca Raton: CRC Press. p. 76. ISBN 0-8493-9118-0. 
  20. ^ Newmark J, Brady RO, Grimley PM, Gal AE, Waller SG, Thistlethwaite JR (October 1981). "Amygdalin (Laetrile) and prunasin beta-glucosidases: distribution in germ-free rat and in human tumor tissue". Proc. Natl. Acad. Sci. U.S.A. 78 (10): 6513–6. doi:10.1073/pnas.78.10.6513. PMC 349070. PMID 6796962. 
  21. ^ Newton GW, Schmidt ES, Lewis JP, Conn E, Lawrence R (February 1981). "Amygdalin Toxicity Studies in Rats Predict Chronic Cyanide Poisoning in Humans". West. J. Med. 134 (2): 97–103. PMC 1272529. PMID 7222669. 
  22. ^ Shragg TA, Albertson TE, Fisher CJ (January 1982). "Cyanide poisoning after bitter almond ingestion". West. J. Med. 136 (1): 65–9. PMC 1273391. PMID 7072244. 
  23. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 91–93.
  24. ^ a b c Laetrile/Amygdalin – National Cancer Institute
  25. ^ US 2985664, Krebs, Ernst T. & Ernst T. Krebs, Jr., "Hexuronic acid derivatives" 
  26. ^ Carpenter, Daniel (2010). Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton: Princeton University Press. Princeton: Princeton University Press. ISBN 0-691-14180-0. 
  27. ^ Kennedy, Donald (1977). "Laetrile: The Commissioner's Decision" (PDF). Federal Register. Docket No. 77-22310. 
  28. ^ American Cancer Society (1991). "Unproven methods of cancer management. Laetrile". CA Cancer J Clin 41 (3): 187–92. doi:10.3322/canjclin.41.3.187. PMID 1902140. 
  29. ^ a b c d e Wade N (December 1977). "Laetrile at Sloan-Kettering: A Question of Ambiguity". Science 198 (4323): 1231–4. doi:10.1126/science.198.4323.1231. PMID 17741690. 
  30. ^ Budiansky, Stephen (1995-07-09). "Cures or Quackery: How Senator Harkin shaped federal research on alternative medicine". U.S. News & World Report. Retrieved 2009-11-07. 
  31. ^ Stock CC, Tarnowski GS, Schmid FA, Hutchison DJ, Teller MN (1978). "Antitumor tests of amygdalin in transplantable animal tumor systems". J Surg Oncol 10 (2): 81–8. doi:10.1002/jso.2930100202. PMID 642516. 
    Stock CC, Martin DS, Sugiura K (1978). "Antitumor tests of amygdalin in spontaneous animal tumor systems". J Surg Oncol 10 (2): 89–123. doi:10.1002/jso.2930100203. PMID 347176. 
  32. ^ a b Milazzo S, Ernst E, Lejeune S, Boehm K, Horneber M (2011). "Laetrile treatment for cancer". Cochrane Database Syst Rev (Systematic review) (11): CD005476. doi:10.1002/14651858.CD005476.pub3. PMID 22071824. 
  33. ^ http://www.cancerhelp.org.uk/about-cancer/treatment/complementary-alternative/therapies/laetrile
  34. ^ Editors of Consumer Reports Books (1980). "Laetrile: the Political Success of a Scientific Failure". Health Quackery. Vernon, New York: Consumers Union. pp. 16–40. ISBN 0-89043-014-4 
  35. ^ Laetrile: The Cult of Cyanide Poisoning; Promoting Poison for Profit, American Journal of Clinical Nutrition, May, 1979, pp. 1121–1158. http://www.ajcn.org/content/32/5/1121.full.pdf retrieved: Jan. 2012.
  36. ^ The Los Angelos Times, April, 1979. http://news.google.com/newspapers?id=bmstAAAAIBAJ&sjid=U4oFAAAAIBAJ&dq=laetrile%20profits&pg=6915%2C1486838 retrieved: Jan. 2012.
  37. ^ Rome News Tribune; March, 1977. http://news.google.com/newspapers?id=ouotAAAAIBAJ&sjid=0zIDAAAAIBAJ&dq=laetrile&pg=4755%2C2326000 retrieved: Jan. 2012.
  38. ^ Moss RW (March 2005). "Patient perspectives: Tijuana cancer clinics in the post-NAFTA era". Integr Cancer Ther 4 (1): 65–86. doi:10.1177/1534735404273918. PMID 15695477. 
  39. ^ Lerner, Barron H. (2005-11-15). "McQueen's Legacy of Laetrile". New York Times. Retrieved 2010-04-23. 
  40. ^ "Dean Burk, 84, Noted Chemist At National Cancer Institute, Dies". Washington Post. 9 October 1988. 
  41. ^ Brian S. McWilliams (2005). Spam kings: the real story behind the high-rolling hucksters pushing porn, pills and @*#?% enlargements. Sebastopol, CA: O'Reilly. ISBN 0-596-00732-9. 
  42. ^ "New York Man Sentenced to 63 Months for Selling Fake Cancer Cure". Medical News Today. 22 June 2004. Retrieved 8 July 2010. 
  43. ^ US FDA (June 22, 2004). Lengthy Jail Sentence for Vendor of Laetrile – A Quack Medication to Treat Cancer Patients. FDA News

References[edit]

External links[edit]