The synethesis of a new
retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide, which has useful
biological properties, is described. This
retinoid was more potent than
retinyl acetate in reversing keratinization caused by
retinoid deficiency in tracheal organ culture. It was markedly less toxic than
retinyl acetate when fed p.o. to rats over 2-week or 6-month periods. It was an effective agent for inhibition of the development of
breast cancer induced in rats by N-nitroso-N-
methylurea, although it was not as potent as
retinyl acetate in this regard. However, the lesser toxicity of
4-hydroxyphenylretinamide makes it a superior agent for prevention of
breast cancer. High-pressure liquid chromatographic analyses of liver and breast extracts from rats treated for 6 months with
retinoids show the pharmacokinetic basis for the superiority of
4-hydroxyphenylretinamide; this
retinoid and its metabolites were found in high concentrations in breast tissue, without any measurable accumulation in the liver or evident liver toxicity. In contrast, chronic feeding of
retinyl acetate caused marked deposition of
retinyl esters in the liver and severe hepatotoxicity. Whole mounts of rat mammary glands, made after chronic feeding of
4-hydroxyphenylretinamide, showed that it had a marked antiproliferative effect on mammary epithelium.