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Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic
by William E. Crist
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Comments by Charles Yanofsky, PhD
The following are comments by Charles Yanofsky, PhD, Department of Biological Sciences, Stanford University, one of the world's leading authorities on tryptophan biosynthesis, responding to questions via email correspondence with William Crist.
Regarding genetically engineered bacteria used to produce higher yields of L-tryptophan
(email — June 2, 1998):
"If Showa Denko engineered the bacterium to overproduce tryptophan [which they did], then there are many unknowns that would be associated with its overproduction. They probably engineered the strain to overproduce chorismate, the common aromatic precursor of tryptophan, as well as to overproduce all of the enzymes of the tryptophan biosynthetic pathway. Overall this would mean that the bacterium is producing large amounts of about 10-15 metabolites that are not normally produced in excess. The accumulation of these metabolites would, in some cases, lead to modification by other enzymes, to give products that normally are never produced by the bacterium. One or more of these unnatural products could be a compound toxic to man.
Similarly the overproduction of enzymes of the aromatic and tryptophan biosynthetic pathways could lead to the synthesis of unnatural products by side reactions that normally do not occur. Again, toxic products could be produced.
Genetic engineering results in the formation of higher than normal concentrations of certain enzymes and products; these could provide the basis for the synthesis of higher levels of toxic substances."
Regarding the FDA and NIH animal study by Love, et al., which suggested that control tryptophan could not be ruled out as an etiological factor in the development of EMS
(email — June 17, 1999):
"If they [toxic products] were produced during purification then it is very unlikely that they would be produced in animals from tryptophan itself. In any event testing high doses of tryptophan (or anything) for long periods in experimental animals is hardly an adequate test. Tryptophan is metabolized by man and important products like serotonin, niacin, and others, are derived from it. Over-administration of any natural metabolite is likely to generate byproducts, which may or may not be toxic. Unless you know exactly how a toxin works, and can perform a valid functional test, it is scientifically unsound to claim that an animal shows what could be the same symptoms from over-administration, and therefore conclude erroneously that the same toxin is produced from tryptophan in animals."
More on over-administration of tryptophan in animals
(email — April 6, 2001):
"Administering a natural metabolite at high doses for an extended period is not a valid test of safety. This procedure might be appropriate for foreign substances which are not known to be metabolized and for which there is no knowledge of the normal levels that are established in the body, but it makes no sense for natural substances that are metabolized. Any natural metabolite if taken in excessive doses or if improperly purified could conceivably be a source of toxic substances that cause serious health problems. In addition, high levels of a metabolite may influence other metabolic pathways. However, administering sensible levels of natural compounds based on known features of metabolism is very unlikely to cause any medical problem, otherwise that problem would exist naturally."
Next: “EMS deaths: Is recombinant DNA technology involved?” The Medical Post, 1990>>
For more information on this subject, see also:
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© Copyright 2005 William E. Crist. All Rights Reserved
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