Codeine (3-methylmorphine) is a known analgesic, antitussive, and antidiarrheal drug that is often abused for recreational purposes. It is metabolized in the liver via the cytochrome P450 system and thus hypothesized to induce hepatic injury especially when misused. Thus, the present study aimed at investigating changes in liver function, hepatic enzyme biomarker, proton pumps, antioxidant status, free radicals and TNF-α levels, as well as caspase 3 activities and hepatic DNA fragmentation after 6 weeks of oral codeine administration. Twenty-one male rabbits were randomized into 3 groups (n = 7). The control group had 1 ml of normal saline, while the low-dose and high-dose codeine groups received 4 and 10 mg/kg b.w of codeine respectively daily. The codeine-treated animals had significantly lower levels of serum proteins, increased activities of hepatic enzyme biomarkers and caspase 3, raised hepatic concentrations of free radicals and TNF-α, as well as increased hepatic DNA fragmentation. Codeine treatment also led to a significant decline in hepatic weight, activities of hepatic enzymatic antioxidant, Na⁺-K⁺-ATPase and Ca²⁺-ATPase. These alterations were more pronounced in high-dose codeine treated animals than in the low-dose group. Histopathological study showed moderate fatty degeneration of hepatic parenchyma, infiltration of the portal tract by inflammatory cells with dense collagen fibre deposition in codeine-treated animals. The present study revealed that codeine induced liver injury and hepatic DNA damage via caspase 3-dependent signaling by suppressing hepatic antioxidant status and enhancing free radical and TNF-α generation.

可待因（3-甲基吗啡）是一种已知的止痛，镇咳和止泻药，经常被用于娱乐目的。它通过细胞色素P450系统在肝脏中代谢，因此被认为可引起肝损伤，尤其是当滥用时。因此，本研究旨在研究口服可待因6周后肝脏功能，肝酶生物标志物，质子泵，抗氧化剂状态，自由基和TNF-α水平以及caspase 3活性和肝DNA片段化的变化。将21只雄性兔随机分为3组（n = 7）。对照组饮用1 ml生理盐水，而低剂量和高剂量可待因组分别每天接受4和10 mg / kg bw可待因。可待因治疗的动物血清蛋白水平明显降低，增加了肝酶生物标志物和caspase 3的活性，增加了肝中自由基和TNF-α的浓度，以及增加了肝DNA片段化。可待因治疗还导致肝脏重量显着下降，肝酶抗氧化剂Na⁺ -K ⁺ -ATPase和Ca ²⁺ -ATPase。在高剂量可待因治疗的动物中，这些改变比低剂量组更明显。组织病理学研究显示，在可待因治疗的动物中，肝实质发生了中等程度的脂肪变性，炎性细胞浸润了门道，致密的胶原纤维沉积。本研究表明可待因通过抑制肝抗氧化剂状态并增强自由基和TNF-α的产生，通过caspase 3依赖性信号传导诱导肝损伤和肝DNA损伤。