Morphine-induced hepatotoxicity in rats: Sex and dose variations in liver enzymes, oxidative stress, inflammation, apoptosis, and histopathology

Abstract

Drug-induced liver injury is a significant cause of acute liver failure, and sex-related biological differences may affect hepatic responses to xenobiotics. This study examined the sex- and dose-dependent effects of morphine on liver function, oxidative stress, inflammation, apoptosis, and histology in Wistar rats. Forty rats (20 males and 20 females) were administered distilled water or morphine at doses of 20, 40, or 60 mg/kg orally once daily for 30 days. Plasma liver enzyme levels and markers of hepatic oxidative stress, inflammation, and apoptosis were assessed, and liver tissues were analyzed histologically. Morphine significantly elevated alanine aminotransferase (ALT) activity in both sexes at most dose levels, with female rats exhibiting greater increases than males at 20 and 40 mg/kg. Alterations in aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) were most pronounced in the low-dose groups. Low-dose morphine also led to significant increases in tumor necrosis factor-alpha (TNF-α), caspase-3, malondialdehyde (MDA), and nitric oxide (NO), indicating enhanced inflammatory, pro-apoptotic, and oxidative responses. While superoxide dismutase (SOD) and catalase (CAT) levels were not significantly altered, glutathione (GSH) demonstrated sex-related variation. Histological analysis revealed that male livers were largely preserved, whereas female livers displayed widened sinusoids and hepatocellular erosion. Overall, morphine induced sex- and dose-dependent hepatotoxicity, with females exhibiting greater susceptibility, particularly at low-dose exposure, which resulted in the most pronounced biochemical disturbances.