一项前瞻性研究评估了对氧磷酶 1 基因型和表型对他汀类药物降脂和抗氧化活性的作用。
A prospective study to assess the role of paraoxonase 1 genotype and phenotype on the lipid-lowering and antioxidant activity of statins.
机构信息
Department of Clinical Pharmacology, Seth G. S. Medical College and KEM Hospital, Mumbai, Maharashtra, India.
Department of Medicine, Seth G. S. Medical College and KEM Hospital, Mumbai, Maharashtra, India.
出版信息
Indian J Pharmacol. 2023 May-Jun;55(3):179-184. doi: 10.4103/ijp.IJP_215_20.
Human paraoxonase 1 (PON1) enzyme protects against atherosclerosis by preventing low-density lipoprotein from oxidative modification. Upregulation of PON1 enzymatic activity is suggested to contribute to atheroprotective potential of statins. Glutamine (Q) to arginine (R) at site 192 and leucine (L) to methionine (M) substitution at site 55 polymorphisms influence the PON1 activity. The study assessed the role of PON1 polymorphisms on lipid-lowering and PON1-modulating activity of statins in a Western Indian cohort of patients with dyslipidemia. Lipid profile and PON1 activity were determined at baseline and 3 months after initiation of statin treatment. PON1 genotypes (QQ, QR, RR; LL, LM, and MM) were determined by PCR-RFLP. Paraoxon was used as a substrate for assessing PON1 activity by spectrophotometry. A total of 140 statin-naïve patients were enrolled; of them, 116 were available for final analysis. Fifty-seven (50%) had QQ, 39 (35%) had QR, and 17 (15%) had RR genotypes. Seventy-six (67%) patients had LL, 35 (31%) had LM, and 2 (2%) had MM genotypes. We observed no impact of PON1 polymorphisms on lipid parameters posttreatment. A significant increase was observed in the serum PON1 activity from a median (range) of 47.92 U/L (9.03-181.25) to 72.22 U/L (7.64-244.44) (P < 0.05) following statin treatment, which was independent from high-density lipoprotein (HDL) concentration. This increase was significantly greater in QQ compared to QR and RR genotypes (P = 0.01). To conclude, the important antioxidant properties of statins are exerted via the rise in serum PON1 activity, independent of HDL cholesterol concentrations. The increase was greater in individuals with QQ genotype. Future large-scale studies will validate the premise that QQ homozygotes see added benefits from statin treatment compared to R carriers. In the meantime, PON1 enzymatic activity remains an important marker to be measured while assessing pleotropic effects of statins in CAD.
人对氧磷酶 1（PON1）酶通过防止低密度脂蛋白氧化修饰来保护动脉粥样硬化。PON1 酶活性的上调被认为有助于他汀类药物的抗动脉粥样硬化作用。位于 192 位的谷氨酰胺（Q）到精氨酸（R）和位于 55 位的亮氨酸（L）到蛋氨酸（M）的取代会影响 PON1 活性。该研究评估了 PON1 多态性在降低血脂和他汀类药物调节 PON1 活性方面在印度西部血脂异常患者队列中的作用。在开始他汀类药物治疗前和治疗 3 个月后测定血脂谱和 PON1 活性。通过 PCR-RFLP 确定 PON1 基因型（QQ、QR、RR；LL、LM 和 MM）。用对氧磷作为分光光度法测定 PON1 活性的底物。共纳入 140 例他汀类药物初治患者；其中 116 例可进行最终分析。57 例（50%）为 QQ，39 例（35%）为 QR，17 例（15%）为 RR 基因型。76 例（67%）患者为 LL，35 例（31%）为 LM，2 例（2%）为 MM 基因型。我们观察到 PON1 多态性对治疗后血脂参数没有影响。与治疗前相比，血清 PON1 活性中位数（范围）从 47.92 U/L（9.03-181.25）显著增加至 72.22 U/L（7.64-244.44）（P<0.05），这与高密度脂蛋白（HDL）浓度无关。与 QR 和 RR 基因型相比，QQ 基因型的增加更为显著（P=0.01）。总之，他汀类药物的重要抗氧化特性是通过血清 PON1 活性的升高发挥作用的，与高密度脂蛋白胆固醇浓度无关。在 QQ 基因型个体中增加更为显著。未来的大规模研究将验证这样一个前提，即与 R 携带者相比，QQ 纯合子从他汀类药物治疗中获得额外益处。同时，PON1 酶活性仍然是评估他汀类药物在 CAD 中的多效性作用时需要测量的一个重要标志物。
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