摘要：Abstract Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of {HPBCD} treatment for {NPC} patients remains to be elucidated. In this study, we examined the acute toxicity of {HPBCD} in Npc1-deficient mice. When treated with {HPBCD} (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1+/+) or Npc1+/− mice died by 72 h after the injection. In contrast, all of the Npc1−/− mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the {HPBCD} treatment in Npc1+/+ or Npc1+/− mice. However, these pathophysiological changes were significantly alleviated in Npc1−/− mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of {HPBCD} in Chinese hamster ovary cells. These results suggest that the {NPC1} genotype exacerbates the cytotoxicity of {HPBCD} and Npc1−/− mice have substantial resistance to the lethality and the organ injury induced by {HPBCD} injection compared with Npc1+/+ or Npc1+/− mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of {HPBCD} using experimental animals and cells.
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