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.