Cytochrome P450 family 46 subfamily A member 1 (CYP46A1) (CYP46A1)

Cytochrome P450 46A1 (CYP46A1), commonly referred to as cholesterol 24-hydroxylase, is a vital enzyme primarily expressed in the brain that regulates cholesterol homeostasis (UniProt: Q9Y6A2). It catalyzes the conversion of cholesterol into 24S-hydroxycholesterol (24S-OHC), the only metabolite of cholesterol that can readily cross the blood-brain barrier to enter the systemic circulation for excretion (PubMed: 10373478). This mechanism is the principal pathway for eliminating excess cholesterol from the central nervous system, as the brain cannot degrade cholesterol locally. Research indicates that CYP46A1 activity is often reduced in neurodegenerative diseases such as Alzheimer's and Huntington's, leading to cholesterol accumulation and subsequent neuronal damage (PubMed: 31511311). Conversely, overactivity or specific metabolic imbalances involving 24S-OHC are implicated in epilepsy, where inhibition of the enzyme by drugs like soticlestat has shown efficacy in reducing seizure frequency (PubMed: 32770150). Consequently, CYP46A1 has emerged as a versatile therapeutic target, with activators like low-dose efavirenz being studied for neuroprotection and inhibitors being developed for refractory epilepsies (PubMed: 23908232). Beyond these roles, the enzyme is also a target of interest in ophthalmology for conditions like glaucoma, where modulating cholesterol levels in the retina may offer therapeutic benefits (PubMed: 28814471).

Other names

Cholesterol 24-hydroxylaseCP46CYP46

Pharmacological activation of CYP46A1 (e.g., by low-dose efavirenz) enhances the conversion of cholesterol to 24S-hydroxycholesterol, promoting cholesterol turnover and reducing toxic accumulation in the brain (PubMed: 23908232). Conversely, inhibition of CYP46A1 (e.g., by soticlestat) is used to reduce 24S-hydroxycholesterol levels, which modulates glutamatergic signaling and provides anti-seizure effects (PubMed: 32770150).