Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury.

Abstract

The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p<0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.