INTRODUCTION
Methotrexate (MTX) is an antifolate drug used to treat rheumatoid arthritis and psoriasis. After conversion to its metabolite 7-hydroxymethotrexate in the liver (Chladek et al., 1997). MTX attaches to hepatocytes as polyglutamate, which leads to a decrease in folic acid levels and an increase in the amount of MTX within the cell (Kamen et al., 1981). However, the clinical use of MTX is often limited by its side effects on various organ systems, particularly the liver.
Long-term use of MTX can activate pathophysiological pathways that cause elevation in liver enzymes, hepatotoxicity, liver fibrosis, and cirrhosis. These pathways include increased oxidative stress, disruption of intracellular ion balance, activation of the immune system, apoptosis, hepatocyte necrosis, and mitochondrial dysfunction. MTX inhibits pyruvate dehydrogenase, 2-oxogluterate dehydrogenase, and cytostolic nicotinamide adenosine diphosphate (NADP)-dependent dehydrogenase. NADP and glutathione reductase enzyme are used to produce reduced glutathione (GSH), which is a protective antioxidant against reactive oxygen species (ROS) (Babiak et al., 1998). It has been reported to cause hepatocyte damage by lowering NADP levels due to MTX use and glutathione levels, which sensitize hepatocytes to reactive oxygen radicals (Uraz et al., 2008).
Ranolazine (RAN) is a drug that has anti-anginal and anti-arrhythmic effects (Chaitman et al., 2004). It regulates intracellular Ca2+ by inhibiting late Na channels in cardiac cells, which may have an antioxidant effect by suppressing the formation of SOR (Song et al., 2006). Recent studies have also shown that RAN has anti-inflammatory effects, inhibiting markers such as C-reactive protein, IL-1, IL-6, and TNF-α (Likozar and Å ebeÅ, 2021). RAN has been shown to inhibit fatty acid uptake and oxidation in the liver by inhibiting cell membrane permeability and mitochondrial electron transfer with pyridine nucleotides (Mito et al., 2010). Moreover, RAN has been found to be effective not only in the heart but also in liver mitochondria, suggesting that it may act on many cells with aerobic metabolism (Wyatt et al., 1995).
As the liver is a metabolic organ where RAN undergoes biotransformation, it is important to suppress oxidative stress mechanisms that cause hepatotoxicity, particularly with the wide use of MTX. Therefore, the aim of this study was to investigate the therapeutic effects of RAN on MTX-induced liver toxicity in terms of oxidative stress, antioxidant capacity, and liver fibrosis.