BLAIR 

 DISCUSSION 



BERRY: I would like to take just a few minutes to tell about 

 some very preliminary findings we have at Bryn Mawr, perhaps 

 relevant to the problem that Dr. Blair emphasized so clearly; 

 the problem of cell anoxia in the patient with septic shock. I 

 want to preface my remarks by recalling my early years as a 

 scientist, the era of vitamin research. Animals were made 

 vitamin deficient and had all sorts of symptoms. It seemed 

 hopeless to find what the vitamin was doing metabolically, be- 

 cause the symptoms were so diffuse, and this is very much the 

 problem with endotoxin. 



Now, the metabolic effects of endotoxin are so diffuse and so 

 wide-spread in an animal, it may be impossible to ever pinpoint 

 the specific enzyme that might be involved. I'm not sure that 

 I have found the enzyme, but I think there is one enzyme in- 

 hibited by endotoxins, and this enzyme is important to the whole 

 well-being of the animal, and may be a valuable clue. The enzyme 

 is tryptophan pyrrolase. It converts tryptophan oxidatively into 

 knyurenine which, in turn, is changed into nicotinamide, which 

 is incorporated in the pyridine nucleotides DPN and TPN. These 

 are the primary hydrogen acceptors in oxidative metabolism, and 

 they are, therefore, directly involved in most of the energy re- 

 lease of the mammalian organism. The reason that I started 

 looking at this enzyme is because the glycocorticoids of the 

 adrenal cortex which are the most effective, if not the only ef- 

 fective compounds capable of protecting animals against endo- 

 toxin, cause a prompt and large increase in tryptophan pyrrolase 

 in the livers of experimental animals. One finds, also, that tryp- 

 tophan will cause an increase in tryptophan pyrrolase, probably 

 as a kind of an adaptive enzyme response. If the enzyme, tryp- 

 tophan pyrrolase, really plays an important role in the pro- 

 tection of an animal against endotoxin, then tryptophan should 

 be about as effective as cortisone in protecting against endotoxin. 

 This was not found with tryptophan, much to our surprise, but 

 it was observed with niacin at a level of 20 jU M, while DPN, 

 at 0.3 /iM, was also active. This is what one would predict if the 



444 



