86 VITAMINS A AND CAROTENES 



large stereoisomeric effects already demonstrated in visual systems, we 

 may expect to find some degree of stereochemical specificity in all the 

 reactions with proteins in which carotenoids participate. 



Since carotenoids isomerize within the body, such effects should be much 

 more limited in the whole animal than in isolated enzyme systems. Never- 

 theless, considerable differences in the over-all effectiveness of various pro- 

 vitamins A fed to rats have been demonstrated in the laboratories of 

 Zechmeister and Deuel. ^'* Stereoisomers of a single carotenoid (e.g., a-caro- 

 tene) were found to vary in biological activity by as much as 400%. In 

 general, the sd\-trans isomer was most active; though pro-7-carotene, a 

 poly-cfs isomer, is about as effective when fed to rats as all-^rans 7-carotene. 



There is good evidence that vitamin A itself stereoisomerizes in the body. 

 It has been reported that neovitamin Aa^^ and the S-cis retinene synthe- 

 sized by Graham et al.^^ yield bioassays comparable Avith aW-trans vitamin 

 A in growth tests in the rat. It has been shown also that, after rats are fed 

 neovitamin Aa, characteristic mixtures of sdl-trans and cis forms of vitamin 

 A are deposited in the liver. ^^ The rate at which vitamin A stereoisomerizes 

 in the body is not known, but it seems at least to keep pace with such long- 

 term processes as growth. Even here, however, on more careful examina- 

 tion, differences have emerged. On reviewing the data which had accumu- 

 lated in the Distillation Products laboratory over a period of seven years, 

 Harris et al.^^ concluded that neovitamin Aa is only 80.7 % as effective 

 as the all-/rans isomer in stimulating growth in rats, and 71.5 % as effective 

 in causing the deposition of vitamin A in the liver. 



The causes of such over-all differences in biological effectiveness are not 

 yet known. They must principally involve early stages in carotenoid metab- 

 olism — differences in stability in the gastrointestinal tract, ease of absorp- 

 tion and transport in the blood, and the first reactions in which these sub- 

 stances take part in the tissues. After a fairly short sojourn in the body, it 

 may be expected that all initial differences in cis-trans configuration are 

 obliterated by stereoisomerization. 



One of the general methods for stereoisomerizing carotenoids is to warm 

 them. At about 60°, many carotenoids form an equilibrium mixture of 

 isomers within 1 to 2 hours.'*^ What takes 1 to 2 hours at 60° might take a 

 day at mammalian body temperature. Perhaps this is all that is involved 

 in the stereoisomerization of carotenoids in vivo. Yet, as already mentioned, 

 there is evidence that in the eye the stereoisomerization of vitamin A or 

 retinene is catalyzed by an enzymatic reaction; and it is possible that else- 

 where in the body enzymes also have a part in stereoisomerizing the caro- 

 tenoids. 



^^ See the review by L. Zechmeister, Vitamins and Hormones 7, 57 (1949). 



«5 W. Graham, D. A. Van Dorp, and J. F. Arens, Rec.trav. chim. 68, 609 (1949). 



66 P. L. Harris, S. R. Ames, and J. H. Brinkman, /. Am. Chem. Sac. 73, 1252 (1951). 



