Nutritional Biochemistry 



Recent evidence has emphasized the import- 

 ance of nutrition at every stage of life. Both pre- 

 natal and postnatal nutrition can permanently affect 

 growth and development, behavior, aging, dis- 

 ease, and other life processes. Advances in the 

 science of nutrition offer great promise for im- 

 proving health, performance, and life expectancy. 

 During the past 10 years, nutritional investigators 

 have made several advances in fundamental scien- 

 tific knowledge. One of the outstanding accom- 

 plishments involves vitamin D. 



Better understanding of the metabolism and 

 functions of vitamin D3 (cholecalciferol) has 

 prompted great interest primarily because of the 

 major significance of the vitamin in a variety of 

 bone diseases. Vitamin D3 is essential for intesti- 

 nal absorption of calcium, but we now know that it 

 is not vitamin D itself that is involved in bone 

 metabolism — it must be metabolically converted 

 first in the liver to 25-hydroxyvitamin D^ and sub- 

 sequently in the kidney to 1,25-dihydroxyvitamin 

 D3 before it can function. This active form should 

 really be considered a hormone rather than a vi- 

 tamin because it is synthesized only in the kidney 

 and acts on a distant target site in intestinal cells, 

 and its production is regulated by a feedback loop 

 involving calcium absorbed in the intestines. Of 

 additional interest is the fact that the metabolic 

 activation of vitamin D3 is regulated physiologi- 

 cally by the need for calcium or phosphorus. 

 Obviously, disease states can result from a dis- 

 ruption of this metabolic activation. 



The major initial finding in vitamin D3 activa- 

 tion was made by Dr. Hector DeLuca and his col- 

 laborators at the University of Wisconsin. They 

 found that cholecalciferol is hydroxylated to 25- 

 hydroxyvitamin D3 by a specific enzyme in the 

 liver, and must then be converted to the fully ac- 

 tive form 1,25-DHCC.The sites of this conversion 

 were the object of intense investigation for a long 

 time. Drs. Fraser and Kodicek in England and 

 Drs. R. J. Midgett, A. Norman, and associates at 

 the University of California, Riverside; Wads- 

 worth Veterans Administration Hospital, Los 

 Angeles; and the UCLA School of Medicine have 

 shown conclusively that the conversion of chole- 

 calciferol to its metabolically active form takes 

 place in the kidney. 



In their research, the investigators found that in 

 individuals with hypoparathyroidism or uremia, 

 the stimulation of intestinal calcium absorption is 

 1,000 times greater when patients are given the 

 active renal metabolite, 1,25-DHCC, than when 

 they are given an equivalent amount of cholecalci- 

 ferol. This finding suggested that the vitamin D- 

 resistant osteomalacia observed in virtually all 



1 04 HEALTH, EDUCATION AND WELFARE 



chronically uremic patients may result from the 

 diseased kidney's inability to convert cholecalci- 

 ferol to the metabolically active form. 



Following this line of research, Drs. A. Nor- 

 man, University of California, Riverside; David 

 Baylink, University of Washington. Seattle; and 

 Jenifer Jowsey, Mayo Foundation, have shown 

 that patients with uremic osteodystrophy (bone 

 degeneration due to kidney dysfunction) respond- 

 ed to small quantities of 1,25-DHCC with benefi- 

 cial changes noted in the plasma electrolytes and 

 in skeletal pathologic findings. Short-term oral 

 administration of 1,25-DHCC to patients with 

 advanced renal failure improved calcium and 

 phosphorous balance, enhanced intestinal calcium 

 absorption, and corrected or improved hypocal- 

 cemia (subnormal blood calcium level). 

 Administration of small quantities of the hormone 

 markedly reversed manifestations of secondary 

 hyperparathyroidism (abnormally increased para- 

 thyroid activity causing loss of calcium from the 

 bones), and improved the previously prominent 

 osteodystrophy. 



The potential of 1,25-DHCC for the treatment 

 of metabolic bone diseases is now being realized, 

 and investigations into this area of nutritional 

 biochemistry are accelerating in an effort to iden- 

 tify its full range of clinical applications. 



In related research. Dr. DeLuca at the Univers- 

 ity of Wisconsin has demonstrated that calcium 

 transport and bone calcium mobilization in ane- 

 phric rats (without kidneys) can be stimulated by 

 chemical analogs of 1,25-DHCC, which have simi- 

 lar chemical structures but are less expensive and 

 less difficult to prepare. Dr. DeLuca and his asso- 

 ciates have found two analogs, 5,6-trans-vitamin 

 D3 and isotachysterol3, that may be useful in the 

 treatment of hypocalcemia, impaired intestinal 

 calcium transport, osteodystrophy due to kidney 

 dysfunction, and secondary hyperparathyroidism. 

 Of the two, isotachysterol3 can be converted and 

 purified more simply and economically, and there- 

 fore holds greater promise for eventual use in 

 cases of renal osteodystrophy. 



Neurosciences 



The promise of the neurosciences has been 

 stressed by the President's Biomedical Research 

 Panel, which concluded its recent report by say- 

 ing, in part: 



Perhaps the ultimate challenge to biomedical 

 research, representing the very pinnacle of our 

 understanding of the human organism, lies in 

 neurobiology: how the brain and nervous sys- 

 tem develop, how they function in health and 

 disease, how thought occurs, how memory is 

 stored, how we reason, how we are motivated, 

 and how we interact with our physical and so- 



