Chemical structure and the changing concept of vitamin A activity.

Studies on chemical structure and vitamin activity have an archaic tang, redolent of the pioneering days of vitamin research, and interest in them has long waned for most vitamins. Vitamin A is an exception, partly because its molecular mode of action (apart from in the visual pigments) is uncertain, but largely because the concept of vitamin A activity has not remained static. The traditional method used to establish the structural requirements for a molecule to show vitamin A activity was the rat growth promotion test: the restoration of growth in animals that have stopped gaining weight on an A deficient diet. From such procedures it was concluded that only limited variation was possible on the retinol molecule (Fig. I , R = CH,OH) if the substance was to manifest more than nugatory vitamin A activity. Some changes were possible at the end of the chain; for example retinoic acid (Fig. I , R = COOH) had growth-promoting activity. Modifications elsewhere in the molecule usually abolished activity or reduced it to a negligible amount (Ames, 1965; Pitt, 1965). The only exceptions to this rule were the 3-dehydro (vitamin A2) series of compounds, with an extra double bond between carbon atoms 3 and 4 in the ring, which had a third to a half of the activity of the corresponding vitamin A, compounds (see references in Pitt,