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Toxic L-tryptophan: Shedding Light on a Mysterious Epidemic
by William E. Crist
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EMS Deaths: Is Recombinant DNA Technology Involved?
By Philip Raphals
The Medical Post (November 6, 1990), Canada
Excerpt from story:
...At this time neither Showa Denko nor FDA are offering any explanation for what caused the concentration of DTAA [Peak E or EBT] and other impurities to rise so dramatically in 1988.
An interesting perspective on the issue was raised by Dr. Charles Yanofsky, professor of biology at Stanford University and a leading expert in the field of tryptophan biosynthesis. He suggests the overproduction of tryptophan may in itself lead to the production of new impurities. Both anthranilic acid and tryptophan are toxic to the bacillus, he said, and bacteria are often capable of adjusting their metabolism to alter toxic substances in their environment.
Since the [genetically] modified bacillus converts anthranilic acid to tryptophan much more rapidly than the parent strain, both substances are present in the culture medium in much higher concentrations than normal.
"It may be that enzymes normally used for some other process start to alter the tryptophan, or that in response to the high concentration of tryptophan, the bacillus starts to produce an enzyme it doesn't normally make," said Dr. Yanofsky.
"Anytime you overproduce a small molecule in bacteria, there are unknowns of this type," he said, where side reactions occur producing unwanted substances.
"The more tryptophan is produced in the cell, the greater the chance that some side reaction will occur at a greater rate, producing more of some contaminant. It's possible that one purification scheme may be quite adequate when producing low levels of tryptophan, but at higher levels, it might not be good enough."
Animal tests
Dr. Yanofsky said the only way to avoid this kind of problem is to perform complete animal tests, using the actual production process. That means identifying all the contaminants, making them in large amounts, and testing them in animals to determine their maximum safe level.
Richard Hinds [a lawyer representing Showa Denko] acknowledged that this type of testing was not undertaken when the more productive strains of bacillus were introduced. Nor would they have been required even it had been regulated as a drug, since the product was already within purity standards. In fact, a number of cases have been reported in Europe, where Showa Denko's tryptophan was sold as a drug...
Reprinted with permission of the author as originally appeared in The Medical Post (November 6, 1990), Canada.
Next: “Japanese Identify Second Impurity in L-tryptophan,” Asahi News Service, June 23, 1992>>
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