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Effects of Pharmacological Retinoids on Several Vitamin A-metabolizing Enzymes¹

Vanderbilt University School of Medicine, Department of Biochemistry, Nashville, Tennessee 37232

Fenretinide (HPR), 13-cis-retinoic acid, and all-trans-retinoic acid are vitamin A derivatives used in the treatment of cancer and severe acne. Patients taking these drugs often show side effects resembling the symptoms of hypovitaminosis A, namely, night blindness and decreased plasma retinol levels. A dietary vitamin A deficiency is not suspected in these patients; therefore, interference with normal vitamin A metabolism seems likely. The effect of these drugs on two enzymes involved in vitamin A metabolism was investigated. At micromolar concentrations, all three derivatives were found to inhibit intestinal lecithin-retinol actyltransferase (LRAT) and to a lesser extent liver LRAT and intestinal retinal reductase. Inhibition of intestinal LRAT by HPR and 13-cis-retinoic acid was enhanced by preincubation prior to assay, whereas inhibition of the other activities was not. The K_i for the inhibition of intestinal LRAT by HPR was determined to be 24.1 ± 5.6 µM. The ability of these drugs to inhibit retinal reduction and retinol esterification in vitro suggests an ability to interfere with normal vitamin A metabolism in vivo, particularly during absorption. This may be most significant for HPR, which is known to accumulate in the liver and intestine after chronic dosing.

¹ This work was supported by NIH grant DK32642.

² To whom requests for reprints should by addressed, at Vanderbilt University, Department of Biochemistry, 610 MRB, Nashville, TN 37232.

Received 8/19/92. Accepted 4/28/93.

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