Identification and characterization of prescription drugs that change levels of 7-dehydrocholesterol and desmosterol

Abstract

Regulating blood cholesterol (Chol) levels by pharmacotherapy has successfully improved cardiovascular health. There is growing interest in the role of Chol precursors in the treatment of diseases. One sterol precursor, desmosterol (Des), is a potential pharmacological target for inflammatory and neurodegenerative disorders. However, elevating levels of the precursor 7-dehydrocholesterol (7-DHC) by inhibiting the enzyme 7-dehydrocholesterol reductase is linked to teratogenic outcomes. Thus, altering the sterol profile may either increase risk toward an adverse outcome or confer therapeutic benefit depending on the metabolite affected by the pharmacophore. In order to characterize any unknown activity of drugs on Chol biosynthesis, a chemical library of Food and Drug Administration-approved drugs was screened for the potential to modulate 7-DHC or Des levels in a neural cell line. Over 20% of the collection was shown to impact Chol biosynthesis, including 75 compounds that alter 7-DHC levels and 49 that modulate Des levels. Evidence is provided that three tyrosine kinase inhibitors, imatinib, ponatinib, and masitinib, elevate Des levels as well as other substrates of 24-dehydrocholesterol reductase, the enzyme responsible for converting Des to Chol. Additionally, the mechanism of action for ponatinib and masitinib was explored, demonstrating that protein levels are decreased as a result of treatment with these drugs.

Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis

“…It is also noteworthy that CAR and ARI are not the only two known inhibitors of DHCR7 [ 13 , 14 , 41 ]. A side effect of elevated 7-DHC levels have been described for a number of commonly prescribed pharmaceutical compounds, including trazodone, haloperidol, sertraline, amiodarone, trifluoperazine, fluphenazine, perphenazine [ 14 , 15 , 41 , 42 ], and various chemicals in our surroundings [ 43 – 45 ]. Undoubtedly, while they are safe and effective compounds for the vast majority of human population, we believe that their effects in the context of patient genotype and life condition (e.g., pregnancy or comorbidity) remains understudied.…”

The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6

“…Although sterols have no effect on DHCR24 protein levels [39], the steroid hormone pregnenolone, and the tyrosine kinase inhibitors masitinib and ponatinib decrease DHCR24 protein levels [69]. DHCR24 enzyme activity can also be decreased by progestin steroid hormones ( progesterone and pregnenolone) [70] and phosphorylation of tyrosine residues [9].…”

Post-translational control of the long and winding road to cholesterol

“…DHCR24 protein levels are similarly unaffected by sterols like cholesterol and 24,25epoxycholesterol (24,25EC) (73), but are decreased by pregnenolone and some tyrosine kinase inhibitors (77). However, these effects on protein levels were observed following 24 h treatment, and may be attributable to transcriptional changes, which tend to occur over longer timeframes.…”