Journal
BIOMOLECULES
Volume 12, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/biom12101535
Keywords
aripiprazole; trazodone; polypharmacy; 7-dehydrocholesterol; 7-dehydrocholesterol reductase; cholesterol; desmosterol; sterols
Categories
Funding
- National Institutes of Health [R01 MH110636, R01 MH067234]
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The combination of the antipsychotic drug aripiprazole (ARI) and the antidepressant drug trazodone (TRZ) inhibits the function of 7-dehydrocholesterol reductase enzyme (DHCR7), leading to disruption of sterol biosynthesis.
Polypharmacy is commonly used to treat psychiatric disorders. These combinations often include drugs with sterol biosynthesis inhibiting side effects, including the antipsychotic aripiprazole (ARI), and antidepressant trazodone (TRZ). As the effects of psychotropic medications are poorly understood across the various tissue types to date, we investigated the effects of ARI, TRZ, and ARI + TRZ polypharmacy on the post-lanosterol biosynthesis in three cell lines (Neuro2a, HepG2, and human dermal fibroblasts) and seven peripheral tissues of an adult mouse model. We found that both ARI and TRZ strongly interfere with the function of 7-dehydrocholesterol reductase enzyme (DHCR7) and lead to robust elevation in 7-dehydrocholesterol levels (7-DHC) and reduction in desmosterol (DES) across all cell lines and somatic tissues. ARI + TRZ co-administration resulted in summative or synergistic effects across the utilized in vitro and in vivo models. These findings suggest that at least some of the side effects of ARI and TRZ are not receptor mediated but arise from inhibiting DHCR7 enzyme activity. We propose that interference with sterol biosynthesis, particularly in the case of simultaneous utilization of medications with such side effects, can potentially interfere with functioning or development of multiple organ systems, warranting further investigation.
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