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N-(4-Hydroxyphenyl)-Retinamide Increases Lecithin:Retinol Acyltransferase Activity in Rat Liver^1,2,

Department of Biochemistry, Medical College of Pennsylvania, Philadelphia, PA 19129 ^* Department of Nutrition, Pennsylvania State University, University Park, PA 16802

N-(4-Hydroxyphenyl)-retinamide (4-HPR; Fenretinide) is a synthetic retinoid which is undergoing investigation as a cancer chemopreventive agent. However, 4-HPR alters vitamin A kinetics and reduces the concentration of plasma retinol. We have conducted studies to examine the effects of 4-HPR on the activity of the enzyme lecithin:retinol acyltransferase (LRAT). This enzyme is implicated in the absorption and storage of vitamin A and is regulated, in liver, by vitamin A nutritional status. To determine whether 4-HPR, like retinoic acid, is able to induce liver LRAT activity, vitamin A-deficient rats having negligible liver LRAT activity were treated with single doses of 4-HPR (0.02–2.5 mg) and liver homogenates were assayed for LRAT activity using ³H-retinol bound to the cellular-retinol binding protein, CRBP, as substrate. Treatment with 4-HPR resulted in a dose- and time-dependent increase in liver LRAT activity which reached a maximum at 24 h. The activity of LRAT assayed in vitro and of hepatic ³H-retinyl ester content determined after an in vivo pulse of ³H-retinol were highly correlated (r = 0.802, P < 0.0002). When vitamin A-sufficient rats were fed a 4-HPR-supplemented diet for 30 d, LRAT activity differed significantly from control values in the liver (P < 0.0001) but not the small intestines. Changes in hepatic retinol metabolism which favor the esterification of vitamin A may be related to the mechanism by which 4-HPR alters vitamin A kinetics in vivo.

KEY WORDS: • retinoic acid • cellular retinol-binding protein • retinol esterification • retinamide • rats • vitamin A

¹ Supported by National Institutes of Health grants DK-46869, HL-22633, and funds from the Howard Heinz Endowment and the Uehara Foundation.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence and reprint requests should be addressed.

Manuscript received 20 March 1996. Revision accepted 12 June 1996.