Involvement of bile salt export pump in flutamide-induced cholestatic hepatitis.

Abstract

The non-steroidal antiandrogen flutamide is widely used for treatment of prostatic cancer, but causes side effects, including cholestatic hepatitis and fulminant hepatitis. We investigated the pathogenesis of flutamide-induced cholestatic hepatitis, focusing on the bile salt export pump (BSEP; ABCB11), which exports bile salts to the bile. We examined the inhibitory effects of flutamide and its active metabolite, hydroxyflutamide, on the transport of taurocholic acid (TCA) by membrane vesicles derived from hBSEP-expressing Sf9 cells. Flutamide inhibited the transport of TCA by hBSEP (IC50 value, about 50 microM), while hydroxyflutamide had no effect at up to 100 microM. When flutamide was administered to rats as a single oral dose of 100 mg/kg, the biliary excretion rate of bolus-injected [3H]TCA was decreased and the liver tissue concentration of flutamide exceeded 50 microM. Repeated doses of flutamide for 5 d (10 mg/kg/d) also decreased the biliary excretion rate of bolus-injected [3H]TCA. In this case, the liver tissue concentration of flutamide was below 0.1 microM. In both cases, no change in the mRNA level of rat Bsep was detected by RT-PCR. These results suggest that flutamide itself, but not its major metabolite, may cause cholestasis by inhibiting BSEP-mediated bile salt excretion.

• Authors: Takashi Iwanaga, Masanori Nakakariya, Hikaru Yabuuchi, Tomoji Maeda, Ikumi Tamai
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 30 Issue 4 Pg. 739-44 (Apr 2007) ISSN: 0918-6158 [Print] Japan
• PMID: 17409513 (Publication Type: Comparative Study, Journal Article)

Chemical References

• ATP-Binding Cassette Transporters
• Androgen Antagonists
• Bile Acids and Salts
• RNA, Messenger
• Taurocholic Acid
• Flutamide

Topics

• ATP-Binding Cassette Transporters (genetics, metabolism)
• Androgen Antagonists (metabolism, pharmacology, toxicity)
• Animals
• Bile Acids and Salts (metabolism)
• Cells, Cultured
• Cholestasis, Intrahepatic (chemically induced, metabolism)
• Dose-Response Relationship, Drug
• Flutamide (metabolism, pharmacology, toxicity)
• Inhibitory Concentration 50
• Male
• RNA, Messenger (analysis, metabolism)
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Spodoptera (cytology, metabolism)
• Taurocholic Acid (blood, metabolism)
• Transport Vesicles (drug effects, metabolism)