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Retinoic Acid: Some aspects of growth-promoting activity in the albino rat¹

Department of Biochemistry, University of Wisconsin, Madison, Wisconsin

On the basis of previous metabolic work it seemed likely that the lower biological activity of retinoic acid is due to its rapid metabolism and excretion as compared with retinol. When retinoic acid dissolved in oil was given orally in small multiple doses (0.5 µg given at 6-hour intervals) to deficient rats, a growth effect resulted which was equivalent to that obtained with a single 2-µg dose of retinol. In contrast, giving retinol in small multiple doses had no additional effect on its apparent biological activity. The effectiveness of a single dose (8 µg) of retinoic acid was increased by 49% when it was administered in two 4-µg portions and by 66% when administered in four 2-µg portions. These results are consistent with the concept that retinoic acid has a lower biological activity than retinol because it is metabolically destroyed more rapidly. A single large dose of retinoic acid (200–500 µg) sustained growth of retinol-deficient rats at a reduced rate for 1 week. However, 3 hours after a 1.5-mg dose of retinoic acid only 2.1% of it was present in liver, 0.94% in intestine and 0.13% in kidney, suggesting that retinoic acid induces some changes or is itself changed into a form which persists for as long as 1 week. In contrast with other reports, vitamin C had no effect on the growth of retinol-deficient rats, which casts doubt on the suggestion that a defect in vitamin C biosynthesis in vitamin A deficiency contributes to the apparent lesions of vitamin A deficiency. Finally, the methyl esters of all-trans and 13-cis retinoic acid were bioassayed for growth in retinol-deficient rats. The 13-cis ester was equal in its growth-promoting activity to all-trans retinoic acid, whereas the all-trans ester was slightly higher in its biological activity.

Manuscript received 9 October 1967.