Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity

P. McCaffery, C. Simons

Research output: Contribution to journalLiterature review

21 Citations (Scopus)

Abstract

All-trans retinoic acid (atRA) is the transcriptionally active product of vitamin A and induces gene expression via specific receptors at nM concentrations. Essential enzymes that regulate the local levels of atRA are the CYP26 members of the cytochrome P450 family, which catabolize atRA. Compounds that have been designed to inhibit these enzymes are known as Retinoic Acid Metabolic Blocking Agents (RAMBAs). Treatment with these compounds will raise endogenous atRA levels and may be therapeutic for the treatment of diseases that respond to high atRA concentrations, including several types of cancer as well as skin conditions such as psoriasis and acne. This review describes the mechanism of action of the RAMBAs and discusses the potential side effects of these compounds. atRA is highly teratogenic and the potential teratogenicity of the RAMBAs is described by comparison with the abnormalities resulting from null mutation of individual CYP26 genes. The possible effects of RAMBAs on the adult brain are also described that have the potential for harm but, in the right circumstances, may also be beneficial.

Original languageEnglish
Pages (from-to)3020-3037
Number of pages18
JournalCurrent Pharmaceutical Design
Volume13
Issue number29
DOIs
Publication statusPublished - Oct 2007

Keywords

  • retinoic acid
  • CYP26
  • catabolism
  • caudal regression
  • limb defect
  • neurogenesis
  • hippocampus
  • embryonal carcinoma-cells
  • central-nervous-system
  • acute promyelocytic leukemia
  • prostate-cancer cells
  • neuroblastoma-cells
  • adult hippocampus
  • vitamin-A
  • in-vitro
  • differential expression
  • 13-CIS-retinoic acid

Cite this

Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity. / McCaffery, P.; Simons, C.

In: Current Pharmaceutical Design, Vol. 13, No. 29, 10.2007, p. 3020-3037.

Research output: Contribution to journalLiterature review

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abstract = "All-trans retinoic acid (atRA) is the transcriptionally active product of vitamin A and induces gene expression via specific receptors at nM concentrations. Essential enzymes that regulate the local levels of atRA are the CYP26 members of the cytochrome P450 family, which catabolize atRA. Compounds that have been designed to inhibit these enzymes are known as Retinoic Acid Metabolic Blocking Agents (RAMBAs). Treatment with these compounds will raise endogenous atRA levels and may be therapeutic for the treatment of diseases that respond to high atRA concentrations, including several types of cancer as well as skin conditions such as psoriasis and acne. This review describes the mechanism of action of the RAMBAs and discusses the potential side effects of these compounds. atRA is highly teratogenic and the potential teratogenicity of the RAMBAs is described by comparison with the abnormalities resulting from null mutation of individual CYP26 genes. The possible effects of RAMBAs on the adult brain are also described that have the potential for harm but, in the right circumstances, may also be beneficial.",
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KW - prostate-cancer cells

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KW - adult hippocampus

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