Pappu Anuradha S, Bacon Sandra P, Illingworth D Roger
Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, L-465, Oregon Health and Science University, Portland, OR 97201, USA.
J Lab Clin Med. 2003 Apr;141(4):250-6. doi: 10.1067/mlc.2003.31.
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitors are widely used to decrease plasma cholesterol levels in patients with heterozygous familial hypercholesterolemia (FH) who are at increased risk of premature coronary artery disease. Tissue-culture and animal studies have indicated that administration of HMG CoA reductase inhibitors (eg, lovastatin, simvastatin, etc) induces a compensatory increase in the activity of HMG CoA reductase, both by increasing its synthesis and decreasing catabolism. To determine in human subjects whether cessation of therapy with this class of drugs leads to induction of HMG CoA reductase activity and above-normal rates of cholesterol biosynthesis, we measured urinary concentrations of mevalonic acid (an indicator of cholesterol biosynthesis) after the cessation of therapy with lovastatin and simvastatin (80 mg/day) in patients with heterozygous FH. Plasma concentrations of LDL increased promptly on discontinuation of reductase inhibitor therapy but did not increase above pretreatment levels at any point after drug discontinuation. Similarly, the 24-hour urinary excretion of mevalonic acid was reduced during treatment with lovastatin or simvastatin and increased promptly on discontinuation of drug but did not increase to levels exceeding those found at baseline when the patients were receiving dietary therapy only. We conclude that cessation of treatment with HMG CoA reductase inhibitors in patients with FH does not result in a rebound increase in cholesterol biosynthesis and that no rebound overshoot occurs in plasma concentrations of low-density-lipoprotein cholesterol.
3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂被广泛用于降低杂合子家族性高胆固醇血症（FH）患者的血浆胆固醇水平，这类患者患早发性冠状动脉疾病的风险增加。组织培养和动物研究表明，给予HMG CoA还原酶抑制剂（如洛伐他汀、辛伐他汀等）会通过增加其合成和减少分解代谢，诱导HMG CoA还原酶活性代偿性增加。为了确定在人类受试者中停用这类药物是否会导致HMG CoA还原酶活性诱导及胆固醇生物合成速率高于正常水平，我们在杂合子FH患者停用洛伐他汀和辛伐他汀（80毫克/天）治疗后，测量了尿中甲羟戊酸（胆固醇生物合成的指标）的浓度。停用还原酶抑制剂治疗后，血浆低密度脂蛋白（LDL）浓度迅速升高，但在停药后的任何时间点均未超过治疗前水平。同样，在用洛伐他汀或辛伐他汀治疗期间，甲羟戊酸的24小时尿排泄量减少，停药后迅速增加，但未增加到超过患者仅接受饮食治疗时的基线水平。我们得出结论，FH患者停用HMG CoA还原酶抑制剂治疗不会导致胆固醇生物合成的反弹增加，低密度脂蛋白胆固醇的血浆浓度也不会出现反弹过高的情况。
