RGD Reference Report - Hydrolysis of 4-HPR to atRA occurs in vivo but is not required for retinamide-induced apoptosis. - Rat Genome Database

RGD Reference Report - Hydrolysis of 4-HPR to atRA occurs in vivo but is not required for retinamide-induced apoptosis. - Rat Genome Database

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General

Hydrolysis of 4-HPR to atRA occurs in vivo but is not required for retinamide-induced apoptosis.
Authors:	Chapman, JS Weiss, KL Curley RW, JR Highland, MA Clagett-Dame, M
Citation:	Chapman JS, etal., Arch Biochem Biophys. 2003 Nov 15;419(2):234-43.
RGD ID:	6771357
Pubmed:	PMID:14592467 (View Abstract at PubMed)
The retinamide, N-(4-hydroxyphenyl)retinamide (4-HPR), has shown promising anti-tumor activity, but it is unclear whether this compound is hydrolyzed to all-trans retinoic acid (atRA) and if so, whether this plays any role in its chemotherapeutic activity. To address this issue, the ability of 4-hydroxybenzylretinone (4-HBR), a carbon-linked analog of 4-HPR, to support growth in vitamin A-deficient (VAD) animals and to activate an atRA-responsive gene in vivo was compared to 4-HPR and atRA. Further, the non-hydrolyzable 4-HBR analog was used to determine whether the presence of the labile amide linkage in 4-HPR is essential for the induction of apoptosis in cultured MCF-7 breast cancer cells. Studies in VAD rats showed that 4-HPR, like atRA, supports animal growth and induces CYP26B1 mRNA expression in lung whereas 4-HBR does not. Analysis of plasma from 4-HPR- and atRA-treated VAD animals revealed the presence of atRA whereas it was not detected in plasma from animals given 4-HBR. To determine whether hydrolysis to atRA is necessary for apoptosis induced by 4-HPR in MCF-7 breast cancer cells, morphological and biochemical assays for apoptosis were performed. 4-HBR, like 4-HPR, induced apoptosis in MCF-7 cells. Apoptosis was not induced even at high concentrations of atRA, showing that 4-HPR and 4-HBR act in cells via a distinct signaling pathway. These results show that although limited hydrolysis of 4-HPR occurs in vivo, the ability to liberate atRA is not required for these 4-hydroxyphenyl retinoids to induce apoptosis in MCF-7 breast cancer cells. Thus the non-hydrolyzable analog, 4-HBR, may have significant therapeutic advantage over 4-HPR because it does not liberate atRA that can contribute to the adverse side effects of drug administration in vivo.

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Molecular Function

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
retinoic acid 4-hydroxylase activity		IMP		6771357		RGD

Objects Annotated

Genes (Rattus norvegicus)

Cyp26b1 (cytochrome P450, family 26, subfamily b, polypeptide 1)

Additional Information