Embryotoxicity of Statins and other Prescribed Drugs with Reported Off-target Effects on Cholesterol Biosynthesis.

Abstract

Cholesterol plays pivotal cellular functions ranging from maintaining membrane fluidity to regulating cell-cell signaling. High cholesterol causes cardiovascular diseases, low cholesterol is linked to neuropsychiatric disorders, and inborn errors of cholesterol synthesis cause multisystem malformation syndromes. Statins lower cholesterol levels by inhibiting the first, rate-limiting reaction of the cholesterol biosynthesis pathway catalyzed by hydroxymethyl-glutaryl-Coenzyme A reductase (HMGCR). However, they have also been shown to interfere with cellular pathways that are unrelated to cholesterol synthesis. One of the last enzymes of cholesterol biosynthesis, 7-dehydrocholesterol reductase (DHCR7), is often mutated in the Smith-Lemli-Opitz syndrome (SLOS), a multisystem malformation syndrome. Strikingly, recent studies have shown that some prescribed psychotropic pharmaceuticals inhibit its activity. In this study, we used Xenopus laevis as a model organism to test the effects of 8 FDA-approved statins and selected prescribed psychotropic drugs on the developing vertebrate embryo. Drugs were tested at concentrations ranging from 0.1µM to 50µM. Embryos were exposed to the drugs from the blastula stage through the swimming tadpole stage with daily medium change. Our data show that statins are heterogenous with respect to their ability to cause embryonic lethality, with simvastatin, pitavastatin, lovastatin, cerivastatin, and fluvastatin being the most toxic ones. Observed phenotypes included delayed development, shortened body axis and pericardiac edema. On the other hand, psychotropic drugs were less embryonic lethal than statins but caused similar phenotypes as well as microcephaly and holoprosencephaly. Our findings suggest that the proximal and distal inhibition of cholesterol biosynthesis have different but overlapping effects on embryonic development.