Tapentadol induces progressive hepatic damage via disrupting Hippo-YAP and bile acid-FXR pathways: An integrated experimental and computational perspective.

Tapentadol (TAP) is a centrally acting analgesic which is broadly used in the management of moderate to severe pain. The current study was conducted to examine the dose-dependent hepatotoxic effects of TAP via evaluating molecular, biochemical, and histopathological parameters. Thirty-two Sprague Dawley rats were divided into four groups i.e., control, TAP (10 mg/kg), TAP (25 mg/kg), and TAP (50 mg/kg) treated group. Our results showed that TAP intoxication upregulated the gene expression of Yes-associated protein 1 (YAP1) while downregulating the gene expression of tumor suppressor kinase 1 (LATS1), mammalian sterile 20-like kinase 1 (MST1), farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP), thereby suggesting a compromise Hippo-YAP signaling and bile acid homeostasis. TAP exposure suppressed the activities of glutathione reductase (GSR), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), hemeoxygenase-1 (HO-1), as well as glutathione S-transferase (GST) coupled with glutathione (GSH) contents while significantly augmented the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Furthermore, TAP intoxication elevated the levels of cholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid, glycocholic acid, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), and Gamma-glutamyltransferase (GGT) while downregulating total protein and albumin. Moreover, TAP induced strong inflammatory and apoptotic responses, which were characterized by an increase in nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), Bcl-2 associated X protein (Bax), cysteine-aspartic acid protease-3 (caspase-3), and cysteine-aspartic acid protease-9 (caspase-9) while inhibition of B cell lymphoma-2 (Bcl-2). Similarly, TAP administration induced severe histopathological alterations including hepatic degeneration, sinusoidal dilation, inflammation, and necrosis. Our findings are further supported by in-silico analysis that showed strong binding affinity of TAP with key regulatory genes. Collectively, these findings suggest that TAP is a hepatotoxic agent and warrant further clinical trials to evaluate its effects in humans.