Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity.
OBJECTIVE
Methotrexate (MTX)-induced hepatotoxicity restricts the clinical use of this immunosuppressive drug. In this study, our aim was to research the role of oxidative stress in the hepatic toxicity of MTX and the protective effect of ursodeoxycholic acid (UDCA) in this setting.


METHODS
Wistar type rats (n = 32) were divided into four groups; group-1 as the MTX + UDCA, group-2 as the MTX, group-3 as the UDCA, group-4 as the saline-receiving groups. The MTX + UDCA and MTX groups of rats received 50 mg/kg of UDCA administered orally; whilst physiological saline was administered orally to the MTX and saline groups and continued for the next 6 days. On the second day of the study, the MTX + UDCA and MTX groups had a single intraperitoneal dose of MTX of 20 mg/kg. The UDCA and saline groups also received similar volumes of physiological saline intraperitoneally. On the sixth day, serum samples were collected and analyzed for ALT, alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) and homogenated liver tissues were examined for reactive oxygen metabolites (ROM); luminol, lucigenin, lipid peroxygenation product malondialdehyde (MDA) and glutathione (GSH) levels.


RESULTS
In the MTX group, serum ALT, ALP, GGT and tissue ROM levels were higher and GSH level was lower. On the histopathological examination, hepatocellular necrosis was clearly more evident in the MTX group than the MTX + UDCA group.


CONCLUSIONS
UDCA treatment protects against MTX-induced liver toxicity. Histopathologically hepatocyte necrosis can be prevented by UDCA treatment, indicating clearly the hepatoprotective effect of this agent on MTX-induced liver injury.
Uraz
Suleyman
S
Department of Gastroenterology, Kocaeli University Medical Faculty, Kocaeli, Turkey.
Tahan
Veysel
V
Aygun
Cem
C
Eren
Fatih
F
Unluguzel
Goksenin
G
Yuksel
Meral
M
Senturk
Omer
O
Avsar
Erol
E
Haklar
Goncagul
G
Celikel
Cigdem
C
Hulagu
Sadettin
S
Tozun
Nurdan
N
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015227:Lipid Peroxidation / Q000502:physiology; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
D002756:Cholagogues and Choleretics; D007166:Immunosuppressive Agents; D014580:Ursodeoxycholic Acid; D008727:Methotrexate