Induction of the oxidative catabolism of retinoic acid in MCF-7 cells

被引:17
作者
Krekels, MDWG
Verhoeven, A
vanDun, J
Cools, W
VanHove, C
Dillen, L
Coene, MC
Wouters, W
机构
[1] JANSSEN RES FDN,DEPT IMMUNOL,B-2340 BEERSE,BELGIUM
[2] JANSSEN RES FDN,DEPT PHARMACOKINET,B-2340 BEERSE,BELGIUM
关键词
oxidative catabolism; induction; retinoic acid; MCF-7; cells; liarozole-fumarate;
D O I
10.1038/bjc.1997.190
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cytochrome P450-dependent oxidation is a pathway for all-trans-retinoic acid (all-trans-RA) catabolism. Induction of this catabolic pathway was studied in MCF-7 breast cancer cells. MCF-7 cells showed low constitutive all-trans-RA catabolism. Concentration-dependent induction was obtained by preincubation of the cells with all-trans-RA (10(-9) to 10(-6) M). Onset of induction was fast, being detectable within 60 min, with maximal induction (45-fold) obtained after 16 h. Enzymatic characterization of induced all-trans-RA catabolism showed an estimated K-m value (Michaelis-Menten constant) of 0.33 mu M and a V-max value (maximal velocity of an enzyme-catalysed reaction) of 54.5 fmol polar all-trans-RA metabolites 10(6) cells(-1) h(-1). These kinetic parameters represent the overall formation of polar metabolites from all-trans-RA. Induction of all-trans-RA catabolism was also obtained with other retinoids, CH55 >> 19-cis-RA = all-trans-RA > 9-cis-RA > 4-keto-all-trans-RA > 4-keto-13-cis-RA > retinol. The potency of the retinoids to induce all-trans-RA catabolism was correlated to their retinoic acid receptor affinity (Crettaz et al, 1990; Repa et al, 1990; Sani et al, 1990). Induction of all-trans-RA catabolism was inhibited by actinomycin D. Furthermore, all-trans-RA did not increase cytosolic retinoic acid-binding protein (CRABP) mRNA levels. These data suggest that induction of all-trans-RA catabolism in MCF-7 cells is a retinoic acid receptor-mediated gene transcriptional event. Induced all-trans-RA catabolism was inhibited by various retinoids with decreasing potency in the order: all-trans-RA > 4-keto-all-trans-RA > 13-cis-RA > 9-cis-RA > 4-keto-19-cis-RA > retinol > CH55. The antitumoral compound liarozole-fumarate inhibited all-trans-RA catabolism with a potency similar to that of all-trans-RA.
引用
收藏
页码:1098 / 1104
页数:7
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