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Defects in cholesterol synthesis genes in mouse and in humans : lessons for drug development and safer treatments
Horvat, Simon ; McWhir, Jim ; Rozman, Damjana, 1960-
This review describes the mouse knockout models of cholesterol synthesis, together with human malformations and drugs that target cholesterogenic enzymes. Generally, the sooner a gene acts in ...cholesterol synthesis, the earlier the phenotype occurs. Humans with loss of function of early cholesterogenic enzymes have not yet been described, and in the mouse, loss of Hmgcr is preimplantation lethal. Together, these results indicate that the widely prescribed cholesterol-lowering strains are potentially teratogenic. The Mvk knockout is early embrionic lethal in the mouse, the absence of Fdft 1 is lethal at E9.5-12.5 dpc, while the Cyp51 knockouts die at 15.5 dpc. Fungal CYP51 inhibitorazoles are teratogenic in humans, potentially leading to symptoms of Antley-Bixler syndrome. The X-linked mutations in Nsdhl and Ebp are embryonic lethal in male mice, while heterozygous females are also affected. Consequently the anticancer drugs, tamoxifen and toremifene, inhibiting human EBP, may be harmful in early pregnancy. The Dhcr7 and Dhcr24 knockout mice die shortly after birth, while humans survive with Smith-Lemli-Opitz syndrome or desmosterolosis. Since cholesterol is essential for hedgehog signaling, disturbance of this pathway by antipsychotics and -depressants explains some drug side effects. In conclusion, defects in cholesterol synthesis are generally lethal in mice, while humans with impairedlater steps of the pathway can survive with severe malformations. Evidence shows that drugs targeting or, by coincidence, inhibiting human cholesterol synthesis are better avoided in early pregnancy. Since drugs with teratogenic potential are successfully on the market, this should also be keptin mind in new cholesterol-related drug development.
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