Metoprolol Inhibits Developmental Brain Sterol Biosynthesis in Mice

Abstract

De novo sterol synthesis is a critical homeostatic mechanism in the brain that begins during early embryonic development and continues throughout life. Multiple medications have sterol-biosynthesis-inhibiting side effects, with potentially detrimental effects on brain health. Using LC-MS/MS, we investigated the effects of six commonly used beta-blockers on brain sterol biosynthesis in vitro using cell lines. Two beta-blockers, metoprolol (MTP) and nebivolol, showed extreme elevations of the highly oxidizable cholesterol precursor 7-dehydrocholesterol (7-DHC) in vitro across multiple cell lines. We followed up on the MTP findings using a maternal exposure model in mice. We found that 7-DHC was significantly elevated in all maternal brain regions analyzed as well as in the heart, liver and brain of the maternally exposed offspring. Since DHCR7-inhibiting/7-DHC elevating compounds can be considered teratogens, these findings suggest that MTP utilization during pregnancy might be detrimental for the development of offspring, and alternative beta-blockers should be considered.

Effects of Psychotropic Medication on Somatic Sterol Biosynthesis of Adult Mice

“…To answer this question confidently, we first need to establish a catalogue of prescription medications with a 7-DHC elevating side effects [ 47 , 48 , 49 ], and try to avoid their simultaneous use [ 2 , 50 , 51 ], especially in patients with the DHCR7 +/- genotype [ 52 ] (who already have a baseline elevation of 7-DHC). However, based on the available data showing that concurrent use of 7-DHC elevating beta-blockers and psychotropic medications [ 53 , 54 ] can have adverse cardiac effects in patients [ 55 ], we suggest that clinical side effects could be related to heart muscle function [ 56 ]. Furthermore, the organ-specific side effects might depend on the exact combination of prescription polypharmacy, defined by the medications’ target organ to a large degree [ 55 , 57 , 58 , 59 ].…”

Chemical Inhibition of Sterol Biosynthesis

“…Additionally, administration of the beta-blocker metoprolol to pregnant mice also inhibits DHCR7 in the brains of newborn pups, increasing 7-DHC and decreasing desmosterol [69]. The DHCR7 inhibition by metoprolol is thought to be part of the mechanism regarding why it has some inhibitory effect on VSV infection in cell culture [50].…”

“…The DHCR7 inhibition by metoprolol is thought to be part of the mechanism regarding why it has some inhibitory effect on VSV infection in cell culture [50]. The newer beta-blocker nebivolol is 10 times more potent in inhibiting DHCR7 in both HepG2 and Neuro2a cell cultures than metoprolol [69].…”