Involvement of Th2 cytokines in the mouse model of flutamide‐induced acute liver injury

Abstract

Drug-induced liver injury is a growing concern for pharmaceutical companies and patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn. Flutamide rarely causes liver dysfunction in humans, and immune allergic reactions have been suggested in some cases. In this study, we investigated the mechanisms of flutamide-induced liver injury in BALB/c mice. Plasma alanine aminotransferase and aspartate aminotransferase levels were significantly increased 3, 6 and 9 h after flutamide (1500 mg kg⁻¹ , p.o.) administration. The biomarker for oxidative stress was not changed, but Th2-dominant immune-related factors, such as interleukin (IL)-4, IL-5, STAT6 and GATA-binding protein (GATA)-3, were induced in flutamide-administered mice. The pre-administration of monoclonal-IL-4 antibody suppressed the hepatotoxicity of flutamide. In addition, we investigated the effect of 13,14-dihydro-15-keto-PGD₂ (DK-PGD₂; 10 µg per mouse, i.p.) administration on flutamide-induced acute liver injury. Coadministration of DK-PGD₂ and flutamide resulted in a significant increase in alanine aminotransferase and a remarkable increase of macrophage inflammatory protein-2. In conclusion, we demonstrated that flutamide-induced acute liver injury is mediated by Th2-dominant immune responses in mice.

Profiles of Serum Cytokines in Acute Drug-Induced Liver Injury and Their Prognostic Significance

“…Experimental models of DILI and retrospective clinical studies [12-15,17-21] have posited immune activation mechanisms associated with acute liver injury. In order to characterize immune components associated with DILI regardless of the pattern and severity of injuries, serum levels of immune analytes were compared among DILI onset (n=78), 6-month follow-up (n=32) and healthy controls (n=40).…”

“…Indeed, several cytokines [12-16], and individual or small groups of cytokines have been reported to be altered in a few experimental studies of DILI [17-21]. For example, in one study in humans, genetic polymorphisms associated with lower production of IL-10, were associated with lower eosinophil counts and poorer outcomes [13].…”

Biomarkers of Flutamide-Bioactivation and Oxidative Stress In Vitro and In Vivo

“…Therefore, a relatively high dose of 500 mg/kg was administered in this study. This dose, however, does not cause overt hepatotoxicity and has been applied by other investigators (McMillian et al, 2004;Coe et al, 2006;Higuchi et al, 2012). Drug plasma concentrations 3 hours after administration in rats were between 35.2 and 57.6 mmol/l (Supplemental Table 1).…”

Adenovirus-Mediated Dual Gene Expression of Human Interleukin-10 and Hepatic Growth Factor Exerts Protective Effect Against CCl4-Induced Hepatocyte Injury in Rats

“…Research on liver injury and injury prevention has long been a focus in the liver disease field. Existing medicine that protects against hepatocyte injury mainly includes cytokines, free radical scavengers, some endogenous and exogenous protective factors, and drugs with membrane-stabilizing effects [20][21][22].…”