EFFECTS OF PHARMACOLOGICAL RETINOIDS ON SEVERAL VITAMIN-A-METABOLIZING ENZYMES

Fenretinide (HPR), 13-cis-retinoic acid, and all-trans-retinoic acid a re vitamin A derivatives used in the treatment of cancer and severe ac ne. 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 meta bolism seems likely. The effect of these drugs on two enzymes involved in vitamin A metabolism was investigated. At micromolar concentration s, all three derivatives were found to inhibit intestinal lecithin-ret inol acyltransferase (LRAT) and to a lesser extent liver 1,RAT and int estinal retinal reductase. Inhibition of intestinal 1,RAT by HPR and 1 3-cis-retinoic acid was enhanced by preincubation prior to assay, wher eas inhibition of the other activities was not. The K(i) for the inhib ition of intestinal LRAT by HPR was determined to be 24.1 +/- 5.6 muM. The ability of these drugs to inhibit retinal reduction and retinol e sterification in vitro suggests an ability to interfere with normal vi tamin A metabolism in vivo, particularly during absorption. This may b e most significant for HPR, which is known to accumulate in the liver and intestine after chronic dosing.