Metabolism of the chemopreventive retinoid N-(4-hydroxyphenyl)retinamide by mammary gland in organ culture

• Published in: Biochemical journal Vol. 256; no. 2; pp. 579 - 584
• Main Authors: Mehta, R.G, Hultin, T.A, Moon, R.C
• Format: Journal Article
• Language: English
• Published: England 01.12.1988
• Subjects: Animals; binding sites; Binding, Competitive; carcinogenesis; Carrier Proteins - metabolism; culture media; Female; Fenretinide; Hormones - pharmacology; mammary glands; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - metabolism; Mice; Mice, Inbred BALB C; Organ Culture Techniques; prevention; Receptors, Retinoic Acid; retinoids; Time Factors; Tretinoin - analogs & derivatives; Tretinoin - metabolism
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj2560579

N-(4-Hydroxyphenyl)retinamide (4-HPR) is considered to be the most effective chemopreventive retinoid for chemically induced mammary carcinogenesis in rats. However, the mechanism of 4-HPR action in mammary cells is poorly understood. In the present study we examined the metabolism of 4-HPR in the mouse mammary gland in organ culture. Mammary glands excised from BALB/c mice were incubated with 4-HPR in the presence of insulin, prolactin and steroid hormones for 6 days. The glands were extracted with chloroform/methanol (2:1, v/v), and the metabolites were separated on a reversed-phase h.p.l.c. column. Three metabolites were separated in addition to 4-HPR; one of the metabolites, M2, was co-eluted with 13-cis-4-HPR, M3 was co-eluted with N-(4-methoxyphenyl)retinamide (4-MPR) and M1 remains unidentified. There appeared to be some hormonal regulation in the distribution of metabolites in the glands. Increased levels of 4-MPR and M1 were observed in insulin-plus-prolactin-treated glands as compared with the glands incubated with steroid hormones. Furthermore, it was observed that M1 isolated from the livers of 4-HPR-treated rats competed for the cellular retinoic acid-binding protein (CRABP) sites; however, 4-HPR did not bind to CRABP. These results indicate that mouse mammary gland can metabolize 4-HPR and that the metabolites which compete for CRABP sites may have physiological significance in the retinoid inhibition of mammary carcinogenesis.