Metabolism of all-trans-retinoic acid in hamster liver microsomes: Oxidation of 4-hydroxy- to 4-keto-retinoic acid

Roberts, Anita B.; Lamb, Lois C.; Sporn, Michael B.

doi:10.1016/0003-9861(80)90293-3

Cited by 115 publications

(51 citation statements)

References 21 publications

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“…In our MCF-7 model system, the catabolites 4-oxo-ATRA and 5,6-epoxy-ATRA were as potent as ATRA at concentrations of 10-8 M and 10-7 M, but were twofold less potent at 10-6 M. It is clear that a complex phenomenon is occurring for which there is no obvious explanation. It is very unlikely that the observed antiproliferative activity of 4-oxo-ATRA and 5,6-epoxy-ATRA was due to conversion back to ATRA as the reactions involved in their formation are irreversible (Roberts et al, 1980;Napoli et al, 1982). Although conversion to other active retinoids is conceivable, such compounds have yet to be identified (Reynolds et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…ATRA metabolism has been studied in a variety of tissues and a number of metabolites have been identified ( Figure 1). One important catabolic pathway for ATRA is initiated by hydroxylation at the four position of the P-ionone ring of ATRA to yield 4-hydroxy-ATRA (Frolik et al, 1979;Roberts et al, 1980). This step is catalysed by a cytochrome P450-dependent ATRA 4-hydroxylase (Roberts et al, 1980;White et al, 1996).…”

mentioning

confidence: 99%

“…One important catabolic pathway for ATRA is initiated by hydroxylation at the four position of the P-ionone ring of ATRA to yield 4-hydroxy-ATRA (Frolik et al, 1979;Roberts et al, 1980). This step is catalysed by a cytochrome P450-dependent ATRA 4-hydroxylase (Roberts et al, 1980;White et al, 1996). 4-Hydroxy-ATRA is further oxidized via 4-oxo-ATRA to more polar metabolites (Roberts et al, 1980).…”

mentioning

confidence: 99%

“…This step is catalysed by a cytochrome P450-dependent ATRA 4-hydroxylase (Roberts et al, 1980;White et al, 1996). 4-Hydroxy-ATRA is further oxidized via 4-oxo-ATRA to more polar metabolites (Roberts et al, 1980). This latter step involves at least one other, presently unknown, cytochrome P450-dependent ously non-enzymatic process (Urbach and Rando, 1994).…”

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confidence: 99%

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All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

heusden

Wouters²,

Ramaekers³

et al. 1998

Br J Cancer

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Summary All-trans-retinoic acid (ATRA) is well known to inhibit the proliferation of human breast cancer cells. Much less is known about the antiproliferative activity of the naturally occurring metabolites and isomers of ATRA. In the present study, we investigated the antiproliferative activity of ATRA, its physiological catabolites 4-oxo-ATRA and 5,6-epoxy-ATRA and isomers 9-cis-RA and 1 3-cis-RA in MCF-7 human breast cancer cells by bromodeoxyuridine incorporation. MCF-7 cells were grown in steroid-and retinoid-free medium supplemented with growth factors. Under these culture conditions, ATRA and its naturally occurring catabolites and isomers showed significant antiproliferative activity in MCF-7 cells in a concentration-dependent manner (10-11 M to 10-M). The antiproliferative activity of ATRA catabolites and isomers was equal to that of the parent compound ATRA at concentrations of 10-M and 1 07 M. Only at 10-6 M were the catabolites and the stereoisomer 1 3-cis-RA less potent. The stereoisomer 9-cis-RA was as potent as ATRA at all concentrations tested (1 0-11 M to 10-M). In addition, we show that the catabolites and isomers were formed from ATRA to only a limited extent. Together, our findings suggest that in spite of their high antiproliferative activity the catabolites and isomers of ATRA cannot be responsible for the observed growth inhibition induced by ATRA.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

heusden

Wouters²,

Ramaekers³

et al. 1998

Br J Cancer

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“…ATRA is rapidly metabolized in a catabolic pathway that includes the 4-hydroxylation of the f-ionone ring to yield 4-hydroxy-ATRA (Frolik et al, 1979, Roberts et al, 1980). This step is catalysed by a cytochrome P450-dependent ATRA 4-hydroxylase (Roberts et al, 1980;White et al, 1996).…”

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confidence: 99%

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

heusden

Wouters²,

Ramaekers³

et al. 1998

Br J Cancer

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SummaryThe clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistance, believed to be caused by increased ATRA catabolism. Inhibitors of ATRA catabolism may therefore prove valuable for cancer therapy. Liarozole-fumarate is an anti-tumour drug that inhibits the cytochrome P450-dependent catabolism of ATRA. ATRA, but also its naturally occurring catabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomers, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanism of action, we investigated whether liarozolefumarate was able to enhance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10-6 M had no effect on MCF-7 cell proliferation. However, in combination with ATRA or the ATRA catabolites, liarozole-fumarate (1 06 M) significantly enhanced their antiproliferative activity. On the contrary, liarozole-fumarate (1 0-6 M) was not able to potentiate the antiproliferative activity of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show that liarozole-fumarate acts as a versatile inhibitor of retinoid catabolism in that it not only blocks the breakdown of ATRA, but also inhibits the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enhancing their antiproliferative activity.

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Analysis of the oxidative catabolism of retinoic acid in rat Dunning R3327G prostate tumors

et al. 1996

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We studied the enzymatic characteristics of the oxidative catabolism of retinoic acid (RA) and its inhibition by liarozole‐fumarate in homogenates of rat Dunning R3327G prostate tumors. Homogenates of rat liver were used as reference material. Both tumor and liver homogenates were able to catabolize retinoic acid. HPLC analysis revealed only very polar metabolites in tumors, while in the liver both metabolites with intermediate polarity and more polar metabolites were found. Kinetic analysis of retinoic acid catabolism showed a Km of 1.7 ± 0.7 μM and a Vmax of 4.2 ± 4.4 pmol polar RA metabolites/mg protein/hr for Dunning G tumor homogenates. In liver homogenates a Km value of 4.3 ± 0.5 μM and a Vmax value of 290 ± 120 pmol polar RA metabolites/mg protein/hr were obtained. Liarozole‐fumarate inhibited retinoic acid catabolism in Dunning tumors and liver with IC50 values of 0.26 ± 0.16 μM and 0.14 ± 0.05, respectively. The results suggest that rat Dunning R3327G tumors are able to metabolize retinoic acid in a manner similar to that found in rat liver but with a lower metabolizing capacity. © 1996 Wiley‐Liss, Inc.

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Metabolism of all-trans-retinoic acid in hamster liver microsomes: Oxidation of 4-hydroxy- to 4-keto-retinoic acid

Cited by 115 publications

References 21 publications

All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

All-trans-retinoic acid metabolites significantly inhibit the proliferation of MCF-7 human breast cancer cells in vitro

The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

Analysis of the oxidative catabolism of retinoic acid in rat Dunning R3327G prostate tumors

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