Chemical Inhibition of Sterol Biosynthesis

Abstract

Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic and nongenetic mechanisms. Hundreds of chemicals that we are exposed to in our daily lives can alter sterol biosynthesis. These also encompass various classes of FDA-approved medications, including (but not limited to) commonly used antipsychotic, antidepressant, antifungal, and cardiovascular medications. These medications can interfere with various enzymes of the post-lanosterol biosynthetic pathway, giving rise to complex biochemical changes throughout the body. The consequences of these short- and long-term homeostatic disruptions are mostly unknown. We performed a comprehensive review of the literature and built a catalogue of chemical agents capable of inhibiting post-lanosterol biosynthesis. This process identified significant gaps in existing knowledge, which fall into two main areas: mechanisms by which sterol biosynthesis is altered and consequences that arise from the inhibitions of the different steps in the sterol biosynthesis pathway. The outcome of our review also reinforced that sterol inhibition is an often-overlooked mechanism that can result in adverse consequences and that there is a need to develop new safety guidelines for the use of (novel and already approved) medications with sterol biosynthesis inhibiting side effects, especially during pregnancy.

Keywords: DHCR24; DHCR7; cholesterol; pharmaceutical inhibition of cholesterol synthesis.

Figure 1

The primary sterol synthesis pathways discussed in this review, demonstrating potential chemical inhibitors for each of the key enzyme steps. * This list is not exhaustive but is meant to demonstrate the breadth of compounds potentially inhibiting each step, including both specific inhibitors and FDA-approved medications (the latter denoted by italics). CYP51A1, cytochrome P450 family 51 subfamily A member 1; LBR, lamin B receptor; SC5D, sterol-C5-desaturase; 7-DHC, 7-dehydrocholesterol; TASIN, truncated adenomatous polyposis coli selective inhibitors.

Figure 2

Chemical structure of selected 7-dehydrocholesterol reductase (DHCR7) inhibitors. Some of these compounds share chemical substructure similarities, while others lack a common structure. Examples of similar structures include 2,3-dichlorophenyl piperazine (2,3-DCPP)—denoted in red—which is shared by aripiprazole and cariprazine, while 4-chlorophenyl-4-hydroxypiperidine (CPHP)—denoted in blue—is common for haloperidol and penfluridol. AY9944 and trazodone are examples of chemicals that share similar, though not identical, structures to other DHCR7-inhibiting chemicals.