Prospective Teratology of Retinoic Acid Metabolic Blocking Agents (RAMBAs) and Loss of CYP26 Activity

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.

Patterning of retinoic acid signaling and cell proliferation in the hippocampus

“…1A,G). The RA catabolic enzymes, Cyp26a1 and Cyp26b1, also control the distribution of RA (McCaffery and Simons,2007). Cyp26b1 but not Cyp26a1 is present in the hippocampus (Abu-Abed et al,2002).…”

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

“…Of those with known function, approximately 15 of the human isoforms that are primarily in families 1, 2, and 3 are involved in the metabolism of xenobiotics (Wienkers and Heath, 2005). Vitamins A and D are metabolized in the brain and kidney by P450s from families 24, 26, and 27 (Sakaki et al, 2005;McCaffery and Simons, 2007), and certain steroid synthesis pathways are carried out by a large number of P450s classified into families 1, 7, 8, 11, 17, 19, 21, 27, 39, 46, and 51 (Miller, 2008). Most of the steroid-oxidizing enzymes are critical for normal physiological function, and their levels are relatively invariable.…”

Local Skin Pharmacokinetics of Talarozole, a New Retinoic Acid Metabolism-Blocking Agent

“…One of the pathways of ATRA inactivation occurs by a CYP26-dependent hydroxylation of the C4 position of the cyclohexenyl ring to form 4-hydroxy-ATRA, which is converted by a reductase into 4-keto-ATRA that is in turn converted to more polar metabolites by microsomal CYPdependent enzymes [23] . In human epidermal keratinocytes, CYP26 appears essential for ATRA catabolism [24] .…”