Comparison of the effects of vitamin A and its analogs upon rabbit ear cartilage in organ culture and upon growth of the vitamin A-deficient rat.

A study was conducted to explore the relationship between the effects of vitamin A upon cartilage and the biological role of vitamin A in maintaining growth and life. Retinol, retinoic acid, alpha-retinoic acid, and ROB-7699 (a cyclopentyl analog of retinoic acid) were highly effective in promoting the lysis of the extracellular matrix of cartilage grown in organ culture in vitro. Retinoic acid and its two analogs were quantitatively more active than was retinol in bringing about lysis of matrix and release of proteoglycan into the culture medium. A bioassay was then conducted to determine the ability of each compound to promote growth of vitamin A-deficient rats. In contrast to their effects upon cartilage, retinoic acid and its two analogs were considerably less active quantitatively than retinol in promoting growth of vitamin A-deficient rats. Moreover, the three acids tested showed graded biological activity in the growth bioassay, with alpha-retinoic acid showing reduced bioactivity (approx. one-fourth that of retinoic acid) and ROB-7699 being virtually inactive. The lysis of cartilage produced by these compounds was presumably caused by release of lysosomal enzymes as a result of the membrane-labilizing effects of the compounds. Thus, these membrane effects of the vitamin A-related compounds are poorly correlated with their biological growth-promoting activity. The alpha-ionone analogs of retinol and retinoic acid were able to maintain good health and growth of vitamin A-deficient rats, although their quantitative activity was low. Rats fed alpha-retinyl acetate showed high liver stores of alpha-retinyl esters and low levels of serum retinol-binding protein (similar to the levels seen in retinoic acid-fed rats). The biological activity of the alpha-ionone analogs was apparently not due to contamination with or conversion to the normal beta-ionone compounds.