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

Purpose: 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. Methods: 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 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Results: 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, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. Conclusions: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.