Research and Development, Department of Pharmacy, Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, India; Department of Pharmacology, KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, Andhra Pradesh, India.
Department of Pharmaceutical Analysis, University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India.
Chem Biol Interact. 2019 Apr 1;302:123-134. doi: 10.1016/j.cbi.2019.02.014. Epub 2019 Feb 19.
Paracetamol (N-acetyl-para amino phenol) is the most commonly used analgesic and antipyretic around the world. Its causes hepatotoxicity and nephrotoxicity at overdose or even at therapeutic doses. It is primarily metabolized by glucuronidation and sulfate conjugation. It is also metabolized by cytochrome-P450 system (CYP2E1, CYP1A2 and CYP 3A4), leading to the formation of N-acetyl-p-benzoquinoneimine (NAPQI). The present study was planned to investigate the influence of chrysin (known CYP2E1 and CYP3A4 inhibitor) on the bioactivation of paracetamol to NAPQI using rat liver microsomes in vitro and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known CYP2E1 inhibitor and chrysin (100 and 200 mg/kg) to rats for 15 consecutive days. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C) of paracetamol were dose-dependently increased with chrysin (100 and 200 mg/kg) compared to paracetamol control group. On the other hand, the AUC and C of NAPQI were decreased significantly with chrysin (100 and 200 mg/kg). The elevated liver and kidney function markers were significantly reduced by chrysin and silymarin compared to paracetamol control group (P < 0.01). Histopathological studies of liver and kidney also well correlated with liver and kidney function tests. Chrysin also reduced the formation of NAPQI in the incubation samples of rat hepatocytes. The present study (both in vivo and in vitro) results revealed that chrysin might be inhibited the CYP2E1, CYP1A2 and CYP3A4-mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.
对乙酰氨基酚（N-乙酰-对氨基苯酚）是全球最常用的止痛和退热药物。过量或甚至在治疗剂量下都会导致肝毒性和肾毒性。它主要通过葡萄糖醛酸化和硫酸盐结合代谢。它也通过细胞色素 P450 系统（CYP2E1、CYP1A2 和 CYP3A4）代谢，导致形成 N-乙酰-对苯醌亚胺（NAPQI）。本研究旨在使用大鼠肝微粒体体外和大鼠体内研究白杨素（已知的 CYP2E1 和 CYP3A4 抑制剂）对扑热息痛生物转化为 NAPQI 的影响。扑热息痛（80mg/kg）连续 15 天口服给予大鼠，不给予或给予水飞蓟素（100mg/kg），一种已知的 CYP2E1 抑制剂和白杨素（100 和 200mg/kg）。与扑热息痛对照组相比，白杨素（100 和 200mg/kg）使扑热息痛的血浆浓度-时间曲线下面积（AUC）和血浆峰浓度（C）呈剂量依赖性增加。另一方面，NAPQI 的 AUC 和 C 显著降低。与扑热息痛对照组相比，白杨素和水飞蓟素显著降低了肝肾功能标志物的升高。肝和肾组织病理学研究也与肝肾功能试验很好地相关。白杨素还降低了大鼠肝细胞孵育样品中 NAPQI 的形成。本研究（体内和体外）结果表明，白杨素可能抑制了 CYP2E1、CYP1A2 和 CYP3A4 介导的扑热息痛代谢；从而减少了 NAPQI 的形成并保护了肝和肾。
