Metabolism of Retinol and Retinoic Acid in N-Methyl-N-nitrosourea-induced Mammary Carcinomas in Rats¹

This study was conducted to examine the in vivo uptake and metabolism of natural retinoids by N-methyl-N-nitrosourea-induced mammary carcinomas. In this study, endogenous retinol and retinyl esters were present in normal mammary epithelial cells, but were undetectable in N-methyl-N-nitrosourea-induced mammary carcinomas in rats as determined by high-pressure liquid chromatography. No differences were found in plasma levels of retinol, in liver retinyl esters, or total content of vitamin A between tumor-bearing and control animals. Administered labeled retinol was taken up and esterified by normal mammary epithelial cells. Tumor-bearing rates were given injections i.p. of either [³H]retinol or [³H]retinoic acid. Radioactivity increased progressively with time in liver and other tissues except in breast tumor, where the uptake fluctuated over the 8 days after the injection of [³H]retinol; in mammary tumors practically no metabolism of [³H]retinol occurred, while in other tissues extensive esterification was detectable. In contrast, in animals given injections of [³H]retinoic acid, the uptake and metabolism of the label in the breast tumors paralleled with those found in other tissues. Neither the activity of acyl coenzyme A:retinol acyl transferase nor the activity of retinyl ester hydrolase was altered in the mammary tumor compared to the normal mammary gland. On the other hand, a significant decrease in the retinal oxidase activity was found in tumor tissue compared to normal mammary tissue. Since no esterification of [³H]retinol occurred in vivo despite the presence of acyl coenzyme A:retinol acyl transferase activity, it is possible that a specific defect in the cellular uptake of retinol may exist in N-methyl-N-nitrosourea-induced mammary carcinomas.