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 retinoic acid receptors (RARs), other mechanisms of action are not excluded. For example, the anti-acne drug, isotretinoin, lacks affinity for the receptors, but is a very potent inhibitor of endogenous vitamin A metabolism in human epidermal cells. To further extend this observation, we studied the effect of 12 different retinoids on the metabolism of [3H]retinol ([3H]ROH) in HeLa cells, previously shown to produce constant levels of 3,4-didehydroretinol (ddROH). The cells were cultured in the presence of the unlabeled retiniods for 20 h, followed by 4 h incubation with [3H]ROH. The accumulation of [3H]ROH and [3H]ddROH in cellular 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 [3H]ROH accumulation and an 80% decrease in [3H]ddROH. Addition of synthetic retinoids with a terminal carboxyl (CD270, CD271, CD367 and Ro 13-7410) decreased the [3H]ddROH accumulation with about 70%, but hardly at all affected the accumulation of [3H]ROH. We conclude that cultured HeLa cells appear to be useful for screening retinoids for their effects on vitamin A metabolism showing that a terminal carboxylic acid is a prerequisite for any major effects on metabolism to occur. Whether this effect is due to interaction with RARs or to competitive inhibition of vitamin-A-metabolizing enzymes demands to be studied.
Stenström
E
E
Department of Dermatology, University Hospital, Linköping, Sweden.
Björklind
C
C
Schaaf
B
B
Vahlquist
A
A
Törmä
H
H
D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006367:HeLa Cells; D006801:Humans; D012176:Retinoids / Q000145:classification* / Q000494:pharmacology* / Q000633:toxicity; D012867:Skin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014801:Vitamin A / Q000378:metabolism*
D012176:Retinoids; D014801:Vitamin A