Hydroxyzine Effects on Post-Lanosterol Biosynthesis in Smith-Lemli-Opitz Syndrome (SLOS) Models

Smith-Lemli-Opitz syndrome (SLOS) is a developmental disability arising from bi-allelic pathogenic variants in the 7-dehydrocholestrol reductase (DHCR7) enzyme and the accumulation of 7-dehydrocholesterol (7-DHC). 7-DHC spontaneously oxidizes and gives rise to cytotoxic oxysterols. Our recent high-throughput screening on Dhcr7-deficient Neuro2a cells identified hydroxyzine (HYZ) as a medication that could counteract the high levels of 7-DHC. We assessed the effects of HYZ in Dhcr7-deficient Neuro2a cells, neuronal cultures and glial cultures from Dhcr7^T93M/T93M transgenic mice, and human dermal fibroblasts from patients with SLOS. LC-MS/MS biochemical analyses revealed a strong modulatory effect of HYZ on post-lanosterol biosynthesis across all four SLOS models. However, the HYZ-induced biochemical changes were complex, dose-dependent, and variable across the four SLOS models. Dhcr7-deficient Neuro2a cells showed decreased 7-DHC, 8-dehydrocholesterol (8-DHC), and desmosterol (DES) levels (all p < 0.01), while neuronal and glial cultures from Dhcr7^T93M/T93M transgenic mice reported 8 significantly altered analytes (all p < 0.001). Human dermal fibroblast from patients with SLOS reacted to HYZ exposure with significantly decreased 7-DHC, 7-dehydrodesmosterol (7-DHD), and dihydrolanosterol (DHL) levels (p < 0.001), coupled with elevation in zymosterol (ZYM), zymostenol (ZYME), and 8-DHC (p < 0.001). Further evaluations are required to determine if the potentially beneficial effects of decreased 7-DHC, 7-DHD and DHL levels in SLOS models and patient biomaterials are counteracted by the rise in other post-lanosterol intermediates.