Bandoh Tsutomu, Sato Eisuke F, Mitani Hironobu, Nakashima Akinori, Hoshi Katsuji, Inoue Masayasu
Department of Clinical Pharmacology, Hokkaido College of Pharmacy, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
Biol Pharm Bull. 2003 Jun;26(6):818-22. doi: 10.1248/bpb.26.818.
We previously reported that fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a strong lipid lowering drug, exerted an anti-atherosclerotic effect at doses insufficient to lower serum lipids in cholesterol fed rabbits. The evidence demonstrated that the superoxide anions from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a critical role in several steps in the development of atherosclerosis. This study was designed to determine the effects of HMG-CoA reductase inhibitors on the production of the superoxide anions of NADPH oxidase in isolated rat peritoneal neutrophils. Fluvastatin (1-10 microM) decreased phorbol 12-myristate 13-acetate (PMA, 10 nM)-dependent reactive oxygen species (ROS) generation in a concentration-dependent manner. It also (10 microM) decreased PMA-dependent O(2) consumption of the rat neutrophils. These effects were reversed by the addition of mevalonate, a metabolite in the HMG-CoA reductase pathway. Treatment with pravastatin did not show any significant changes. Fluvastatin (10 microM) decreased ROS, such as hydroxyl radicals and superoxide anions generated by the Fenton reaction, and by the xanthine-xanthine oxidase system. Rats were treated with either fluvastatin (5 mg/kg per day, p.o.) or pravastatin (5 mg/kg per day, p.o.) for 1 week. Treatment with fluvastatin decreased the PMA-dependent ROS generation. The fluvastatin induced effect on the PMA-dependent ROS generation was reversed by the combined administration with 40 mg/kg mevalonate per day. The antioxidative effect of fluvastatin was thought to have caused not only the scavenging action of the radicals but also to have inhibited ROS generation by inhibiting the NADPH oxidase activity. This antioxidative potential of fluvastatin via the inhibition of NADPH oxidase activity may be profitable in preventing atherosclerosis.
我们之前报道过，氟伐他汀是一种强效的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，一种强力降脂药物，在喂食胆固醇的兔子中，其剂量不足以降低血脂时就能发挥抗动脉粥样硬化作用。有证据表明，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生的超氧阴离子在动脉粥样硬化发展的几个步骤中起关键作用。本研究旨在确定HMG-CoA还原酶抑制剂对分离的大鼠腹腔中性粒细胞中NADPH氧化酶超氧阴离子产生的影响。氟伐他汀（1-10微摩尔）以浓度依赖的方式降低佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA，10纳摩尔）诱导的活性氧（ROS）生成。它还（10微摩尔）降低了大鼠中性粒细胞中PMA依赖的氧气消耗。添加甲羟戊酸（HMG-CoA还原酶途径中的一种代谢产物）可逆转这些作用。普伐他汀治疗未显示任何显著变化。氟伐他汀（10微摩尔）降低了由芬顿反应以及黄嘌呤-黄嘌呤氧化酶系统产生的ROS，如羟基自由基和超氧阴离子。大鼠每天口服氟伐他汀（5毫克/千克）或普伐他汀（5毫克/千克），持续1周。氟伐他汀治疗可降低PMA依赖的ROS生成。每天联合给予40毫克/千克甲羟戊酸可逆转氟伐他汀对PMA依赖的ROS生成的诱导作用。氟伐他汀的抗氧化作用被认为不仅是由于自由基的清除作用，还通过抑制NADPH氧化酶活性抑制了ROS生成。氟伐他汀通过抑制NADPH氧化酶活性所具有的这种抗氧化潜力可能对预防动脉粥样硬化有益。
