Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity.
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.
McCaffery
P
P
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. p.j.mccaffery@abdn.ac.uk
Simons
C
C
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D000072516:Retinoic Acid 4-Hydroxylase; D018600:Teratology / Q000639:trends; D044024:Tetralones / Q000737:chemistry / Q000633:toxicity; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D044024:Tetralones; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase