Baykan, Ahmed Ramiz; Cerrah, Serkan; Kartal Baykan, Emine; Tanas, Serdar; Yavuzer, Bulent; Yazici, Gulce Naz; Kuzucu, Mehmet; Altuner, Durdu; Suleyman, Halis

Background: Olaparib, a clinically established poly (ADP-ribose) polymerase (PARP) inhibitor widely used in oncology, has significantly improved outcomes in several malignancies. However, increasing evidence indicates that olaparib may induce hepatocellular injury through mechanisms involving oxidative stress, inflammation, and mitochondrial dysfunction. Adenosine triphosphate (ATP), a key regulator of cellular bioenergetics and redox homeostasis, may confer protection against oxidative tissue injury. This study investigated the hepatoprotective effects of ATP against olaparib-induced oxidative liver damage in rats and compared its efficacy with melatonin. Methods: Twenty-four male albino Wistar rats were randomly assigned to four experimental groups (n = 6): healthy control (HG), olaparib-treated (OLP), ATP plus olaparib (ATOL), and melatonin plus olaparib (MLOL). Olaparib was administered at a dose of 100 mg/kg orally twice daily, whereas ATP (5 mg/kg, intraperitoneally) and melatonin (10 mg/kg, orally) were administered once daily. The treatments were administered for 14 consecutive days. Hepatic oxidative and inflammatory status was assessed by measuring malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT), interleukin-6 (IL-6) and ATP levels in liver tissue. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were measured as biochemical indicators of hepatocellular injury. Liver tissues were also examined histopathologically. Results: Olaparib administration significantly increased hepatic MDA and IL-6 levels together with serum ALT and AST activities, while significantly reducing hepatic tGSH and ATP levels and SOD and CAT activities compared with the healthy group (p < 0.001). Both ATP and melatonin significantly attenuated these alterations (p < 0.001). Notably, ATP demonstrated a more pronounced protective effect than melatonin, particularly in suppressing aminotransferase elevations and improving histopathological liver architecture. Conclusion: ATP significantly alleviates olaparib-induced hepatotoxicity by attenuating oxidative stress, suppressing inflammatory responses, restoring antioxidant defense mechanisms and significantly replenishing depleted hepatic ATP levels. These findings suggest that ATP may represent a promising therapeutic strategy for preventing PARP inhibitor-associated drug-induced liver injury.

Paltaci, Seyma Ilayda; Yilmaz, Nesrin; Kozali Uzun, Sukran; Yavuzer, Bulent; Coban, Taha Abdulkadir; Ozkaraca, Mustafa; Gungor, Ali; Yaqubov, Kamandar; Suleyman, Halis

Background: Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor used to treat several malignancies. Previous studies have reported that olaparib may induce ovarian injury by elevating reactive oxygen species and impairing cellular energy homeostasis. ATP is a central regulator of intracellular energy balance and antioxidant defense, whereas thiamine pyrophosphate (TPP), the active form of vitamin B1, supports ATP biosynthesis and possesses antioxidant and anti-inflammatory properties. This study compared the protective effects of ATP and TPP against olaparib-induced ovarian injury in rats. Methods: Twenty-four female Wistar albino rats were randomly assigned to four groups (n=6 each): healthy control (HG), olaparib-only (OLP), ATP plus olaparib (ATOL), and TPP plus olaparib (TPOL). Olaparib (100 mg/kg, orally, twice daily), ATP (5 mg/kg, intraperitoneally, once daily), and TPP (25 mg/kg, intraperitoneally, once daily) were administered for 14 consecutive days. Ovarian tissue levels of oxidant (MDA), antioxidants (tGSH, SOD, CAT), and pro-inflammatory cytokine (IL-6) were determined. Tissue specimens underwent histopathological (follicular and parenchymal degeneration) and double immunofluorescence analyses (IRE1α, cleaved Caspase-3, LC3B, and NF-κB p65 immunopositivity). Results: Olaparib significantly increased oxidant and pro-inflammatory cytokine levels and decreased antioxidant levels. Histopathology revealed severe follicular and parenchymal degeneration, and immunofluorescence analysis showed significantly increased IRE1α, cleaved Caspase-3, LC3B, and NF-κB p65 immunopositivity. Both ATP and TPP pre-treatment significantly attenuated olaparib-induced oxidative stress, inflammatory responses, histopathological injury, and cellular stress marker immunopositivity. ATP demonstrated a more pronounced protective effect than TPP, particularly regarding follicular degeneration suppression and LC3B and NF-κB p65 immunopositivity. Conclusion: Olaparib induced ovarian injury accompanied by oxidative stress, cytokine-mediated inflammation, IRE1α-related endoplasmic reticulum stress, cleaved Caspase-3-related apoptosis, LC3B-related autophagy, and NF-κB-related inflammatory signaling. Both ATP and TPP attenuated olaparib-associated injury, with greater effects for ATP. These findings suggest that maintenance of cellular energy homeostasis may represent a promising strategy for attenuating PARP inhibitor-induced ovarian injury.