Medication-induced disruption of sterol biosynthesis poses significant risks to brain development and function. (IMAGE)
Caption
Medication-induced disruption of sterol biosynthesis poses significant risks to brain development and function. At the top center of this schematic lies the cholesterol molecule—an anchor of neurobiological integrity—flanked by the structure of haloperidol embedded within the brain, exemplifying one of over
30 FDA-approved compounds known to inhibit DHCR7. These agents, many of which are orally administered and processed through the gastrointestinal–hepatic axis, initiate biochemical disruptions at the level of first-pass metabolism, altering sterol homeostasis before the compounds even reach the central nervous system. The result: accumulation of toxic precursors such as 7-dehydrocholesterol (7-DHC) and their conversion into highly reactive oxysterols (top right), with well-established neurotoxic potential. On the left, a DNA strand signals genetic vulnerability,which can amplify these pathological cascades—particularly during periods of neurodevelopmental sensitivity (lower right). The diverse array of medications (pills, upper left) underscores the wide pharmacologic footprint of this off-target effect, raising serious concerns about additive or synergistic toxicity in the context of polypharmacy. Taken together, this mechanism—once overlooked—demands urgent attention as a pressing public health concern, particularly for developing brains and genetically susceptible populations.
Credit
Julio Licinio
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