Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2023 May;27(10):4718-4734. doi: 10.26355/eurrev_202305_32484.
Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a pregnane X receptor (PXR) agonist that increases the expression of xenobiotic transporters with anti-inflammatory and antioxidant potential. Thus, we hypothesized that pregnenolone would protect against DOX-induced hepatotoxicity.
Male Wistar rats (180-200 g) were randomized into four groups (n = 7): Control, Control + Pregnenolone (35 mg/kg/day, orally), DOX (15 mg/kg, i.p.) single dose on day five, and Pregnenolone + DOX. All treatments continued for seven consecutive days. Twenty-four hours after the last treatment, serum and liver tissues were collected for biochemical and histopathological assessment. The possible interaction between pregnenolone and DOX on cell viability was tested in HepG2 cells in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
DOX treatment resulted in hepatic damage and fibrosis with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples of the DOX-treated group showed increased oxidative stress [malondialdehyde (MDA) and total nitrite/nitrate and decreased reduced glutathione (GSH) and superoxide dismutase (SOD)], increased hepatic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-β1), and mRNA of interleukin-1beta (IL-1β) and interleukin-6 (IL-6). Pretreating the rats with pregnenolone antagonized these DOX-induced effects. Moreover, pregnenolone upregulated the hepatic expression of Nrf2, heme oxygenase-1 (HO-1), and P-glycoprotein and decreased Keap1, opposing the effects of DOX. Moreover, pregnenolone prevented the DOX-induced activation and nuclear translocation of NFκB and increased cleaved caspase-3. Pregnenolone potentiated DOX-mediated cytotoxicity in HepG2 cells.
These results illustrate the protective effects of pregnenolone against DOX-induced hepatotoxicity without limiting its anticancer activity.
多柔比星（DOX）是一种广泛使用的细胞毒性蒽环类抗生素，其特点是不良反应增加，限制了其临床应用。孕烯醇酮是一种孕烷 X 受体（PXR）激动剂，可增加具有抗炎和抗氧化潜力的外源性转运体的表达。因此，我们假设孕烯醇酮可以预防 DOX 诱导的肝毒性。
雄性 Wistar 大鼠（180-200g）随机分为四组（n=7）：对照组、对照组+孕烯醇酮（35mg/kg/天，口服）、DOX（15mg/kg，腹腔注射）单次剂量于第 5 天，以及孕烯醇酮+DOX。所有治疗均连续进行 7 天。最后一次治疗后 24 小时，收集血清和肝组织进行生化和组织病理学评估。体外通过 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物（MTT）测定法在 HepG2 细胞中测试孕烯醇酮和 DOX 对细胞活力的可能相互作用。
DOX 治疗导致肝损伤和纤维化，血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）升高。DOX 处理组的肝组织显示氧化应激增加[丙二醛（MDA）和总亚硝酸盐/硝酸盐以及还原型谷胱甘肽（GSH）和超氧化物歧化酶（SOD）减少]，肝肿瘤坏死因子-α（TNF-α）、白细胞介素-10（IL-10）、转化生长因子-β1（TGF-β1）和白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的 mRNA 水平增加。用孕烯醇酮预处理大鼠可拮抗这些 DOX 诱导的作用。此外，孕烯醇酮上调了肝脏 Nrf2、血红素加氧酶-1（HO-1）和 P-糖蛋白的表达，并降低了 Keap1，从而拮抗了 DOX 的作用。此外，孕烯醇酮可防止 DOX 诱导的 NFκB 激活和核转位，并增加 cleaved caspase-3。孕烯醇酮增强了 HepG2 细胞中 DOX 介导的细胞毒性。
这些结果表明，孕烯醇酮对 DOX 诱导的肝毒性具有保护作用，而不会限制其抗癌活性。
