RETINOIDS CAN BE CLASSIFIED ACCORDING TO THEIR EFFECTS ON VITAMIN-A METABOLISM IN HELA-CELLS

Although retinoids may exert their action via binding to nuclear retin oic acid receptors (RARs), other mechanisms of action are not excluded . For example, the anti-acne drug, isotretinoin, lacks affinity for th e receptors, but is a very potent inhibitor of endogenous vitamin A me tabolism in human epidermal cells. To further extend this observation, we studied the effect of 12 different retinoids on the metabolism of [H-3]retinol ([H-3]ROH) in HeLa cells, previously shown to produce con stant levels of 3,4-didehydroretinol (ddROH). The cells were cultured in the presence of the unlabeled retinoids for 20 h, followed by 4 h i ncubation with [3H]ROH. The accumulation of [3H]ROH and [3H]ddROH in c ellular extracts was analysed by HPLC. Addition of 10(-10) to 10(-5) M of four naturally occurring isomers of retinoic acid caused a 4- to 6 -fold increase in [H-3]ROH accumulation and an 80% decrease in [H-3]dd ROH. Addition of synthetic retinoids with a terminal carboxyl (CD270, CD271, CD367 and Ro 13-7410) decreased the [H-3]ddROH accumulation wit h about 70%, but hardly at all affected the accumulation of [H-3]ROH. We conclude that cultured HeLa cells appear to be useful for screening retinoids for their effects on vitamin A metabolism showing that a te rminal carboxylic acid is a prerequisite for any major effects on meta bolism to occur. Whether this effect is due to interaction with RARs o r to competitive inhibition of vitamin-A-metabolizing enzymes demands to be studied.