Original Article

Cytotoxicity of flutamide and 2-hydroxyflutamide and their effects on CYP1A2 mRNA in primary rat hepatocytes.

Authors: Hai-Xue WANG, Xiao-Chao MA, Qiao-Lin DENG, Duan LI

Abstract

AIM: To compare the cytotoxicity of flutamide and its active metabolite
2-hydroxyflutamide and their effects on cytochrome P-450 1A2 mRNA in primary rat
hepatocytes.
METHODS: After the isolation of hepatocytes a nd t he primary incubation for 4 h,
flutamide and 2-hydroxyflutamide were added respectively to the medium at the
concentration of 10, 20, and 50 mg/L and incubated for 8 h. Cytotoxicity of
hepatocytes was assessed by Trypan blue exclusion, lactate dehydrogenase (LDH)
leakage, percentage of alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) release, and reduced glutathione (GSH). The effect of
flutamide and 2-flutamide on the CYP1A2 mRNA level was further analyzed by
Northern blot.
RESULTS: After incubation for 8 h, cell viability was observed by Trypan blue
exclusion. The increase of ALT and AST activity and the decrease of glutathione
content were also noted at 10, 20, and 50 mg/L of flutamide and 50 mg/L of
2-hydroxyflutamide as compared with normal rat hepatocytes. Induction of CYP1A 2
mRNA were 2-, 5-, and 7.5-fold at 10, 20, and 50 mg/L of flutamide and 3.5-fold
at 50 mg/L of 2-hydroxyflutamide.
CONCLUSION: Cytotoxicity of flutamide and its effect on CYP1A2 mRNA were stronger
than those of its active metabolite 2-hydroxyflutamide in primary rat
hepatocytes.
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