Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study
| Autor: | Junbo Ge, Qiongyang Yu, Zhen Dong, Jian An, Yijing Lu, Xiurui Ma, Xunde Xian, George Liu, Yuhui Wang, Aijun Sun, Haozhe Shi, Yunan Wang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Statin medicine.drug_class Atorvastatin Hamster 030204 cardiovascular system & hematology Pharmacology Cholesterol Dietary 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cricetinae medicine Animals Humans Pharmacology (medical) Rosuvastatin Rosuvastatin Calcium biology Cholesterol business.industry nutritional and metabolic diseases Cytochrome P450 General Medicine Middle Aged Disease Models Animal 030104 developmental biology chemistry LDL receptor Toxicity biology.protein Female lipids (amino acids peptides and proteins) Chemical and Drug Induced Liver Injury Hydroxymethylglutaryl-CoA Reductase Inhibitors Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | Cardiovascular Drugs and Therapy. 35:367-380 |
| ISSN: | 1573-7241 0920-3206 |
| Popis: | Statins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which is involved in cholesterol synthesis. The major side effects of statins include muscle- and liver-related toxicity. Muscle toxicity is highly associated with polymorphisms in cytochrome P450 proteins (CYPs), as predicted by pharmacogenomics. However, the mechanisms of hepatotoxicity are not well understood. Due to differences in cholesterol metabolism, statins are well tolerated in mice. In contrast, hamsters exhibit metabolic traits similar to humans and are suitable for studying the hepatotoxicity of statins. We investigated the effect of rosuvastatin (RSV) on liver damage in wild-type (WT) hamsters fed a high-cholesterol diet (HCD) and LDLR knockout (LDLR−/−) hamsters that developed spontaneous hypercholesterolemia. Two cohorts of clinical subjects (clinical registry number: 2017001) taking atorvastatin (ATV) were recruited for direct (assessment of cholesterol intake individually, n = 44) and indirect (celebratory meals/holiday season, n = 1993) examination of dietary cholesterol intake and liver damage, as indicated by elevation of alanine aminotransferase (ALT). RSV at a dose of 10 mg/kg caused fatal liver damage only in HCD-fed WT hamsters, while LDLR−/− hamsters with the same cholesterol levels were resistant to this toxic effect. In the human studies, we observed that the incidence of hepatic toxicity in patients receiving long-term ATV treatment was higher in patients with greater dietary cholesterol intake and in patients who consumed more food during Chinese holidays. Our results propose, for the first time, that dietary cholesterol significantly contributes to statin-related hepatotoxicity, providing valuable insight into the clinical use of statins. |
| Databáze: | OpenAIRE |
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