CYP4A12B Activators

CYP4A12B, a key enzyme in the arachidonic acid omega-hydroxylase pathway, plays a crucial role in the metabolism of arachidonic acid, enabling arachidonic acid omega-hydroxylase activity. Predicted to be located in the apical plasma membrane, endoplasmic reticulum membrane, and extracellular space, CYP4A12B is active in intracellular membrane-bounded organelles. Its expression in the metanephros, nervous system, nose, and respiratory system underlines its diverse physiological roles. The human ortholog(s) of CYP4A12B are implicated in hypertension, emphasizing the enzyme's potential involvement in cardiovascular health. Activation of CYP4A12B involves a variety of chemicals that either directly or indirectly modulate its activity. Clofibrate, as a direct activator, binds to peroxisome proliferator-activated receptor alpha (PPARα), leading to increased transcription of CYP4A12B and enhanced omega-hydroxylase activity. ATRA indirectly activates CYP4A12B by modulating retinoic acid receptor (RAR) signaling, while butylated hydroxyanisole (BHA) indirectly activates the enzyme by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ).

Substrates such as 12(S)-HETE and 20-HETE directly stimulate CYP4A12B by acting as substrates and product feedback activators, promoting enzymatic activity in the omega-hydroxylase pathway. Chemicals like GW501516 and lithocholic acid act as indirect activators through PPARδ and farnesoid X receptor (FXR) modulation, respectively. Phenobarbital, by interacting with the constitutive androstane receptor (CAR), directly activates CYP4A12B, while leukotriene C4 serves as a substrate and autoregulatory activator. TGF-β acts as an indirect activator by modulating Smad signaling, leading to increased gene expression and enhanced omega-hydroxylase activity. Ketoconazole, while inhibiting CYP4A12B, induces compensatory upregulation of enzyme expression. Diethylhexyl phthalate (DEHP) indirectly activates CYP4A12B through PPARα modulation, emphasizing the diversity of pathways involved in the enzyme's regulation. Understanding the complex regulatory network governing CYP4A12B activation is crucial for deciphering its role in arachidonic acid metabolism and its potential implications in cardiovascular health. The identified chemicals provide valuable insights into the specific pathways and receptors influencing CYP4A12B, paving the way for further research into its functional significance in maintaining cellular homeostasis.