All-trans retinoic acid mitigates methotrexate-induced liver injury in rats; relevance of retinoic acid signaling pathway

Abstract

Methotrexate (MTX) is a widely used drug for treatment of rheumatic and autoimmune diseases as well as different types of cancer. One of the major side effects of MTX is hepatotoxicity. Retinoid receptors, including retinoid X receptor (RXR), and retinoic acid receptor (RAR) are vitamin A receptors that are highly expressed in the liver and regulate important physiological processes through regulation of different genes. In this study, we investigated the effect of MTX on RXR-α and RAR-α expression in the liver and the potential protective effects of all-trans retinoic acid (ATRA) in MTX-induced hepatotoxicity. Rats were randomly divided into five groups: The rates were treated with saline, DMSO, MTX (20 mg/kg/IP; single dose), ATRA (7.5 mg/kg/day, I.P), or MTX and ATRA. Rats were killed 24 h after the last ATRA injection. The liver tissues were dissected out, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Our results demonstrated that treatment with MTX resulted in significant decrease in reduced glutathione (GSH) content and superoxide dismutase (SOD) activity, with concomitant increase in ALT, AST, and MDA levels. In addition, MTX markedly downregulated the expression of both RXR-α and RAR-α, and changed the appearance of RXR-α to be very small speckled droplets. Treatment with ATRA significantly ameliorated MTX-induced effects on GSH, ALT, and MDA. Moreover, ATRA administration increased the expression and nuclear translocation of RXR-α in rat hepatocytes. In conclusion, our study revealed, for the first time, that retinoid receptors may play an important role in the MTX-induced hepatotoxicity.

ω-3 fatty acids as an adjuvant therapy ameliorates methotrexate-induced hepatotoxicity in children and adolescents with acute lymphoblastic leukemia: A randomized placebo-controlled study

“…Black seed oil decreased MTX hepatotoxicity and improved survival in children with ALL [56]. Treatment with all-trans retinoic acid significantly ameliorated MTX-induced hepatic effects on glutathione, ALT, and MDA [57]. Similar results were obtained using coenzyme Q10 [58].…”

Histopathological and biomedical parameters determination in the protective effect of crocin on hepatotoxicity induced by methotrexate in rats

“…Incidence of necrosis or cell-membrane damage of hepatocytes causes release of these enzymes into the bloodstream (10). It seems that Met causes liberation of receptors as speckled droplet through down-regulation of RAR-α, where these receptors can cause induction of hepatic damage (28). It seems that Cro causes stability of cellular membranes through prevention of lipid peroxidation and enzymatic leakage (17).…”

Protective Effect of All-Trans Retinoic Acid in Cisplatin-Induced Testicular Damage in Rats

“…ATRA was dissolved in pure corn oil, and no solvent was used for CP. The ATRA and CP doses as well as administration times were specified according to similar previous studies [81011].…”