Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.17.3.2 (
xanthine oxidase
)
8,383
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Flutamide is used for prostate cancer therapy but occasionally induces severe liver injury. Flutamide is hydrolyzed in the body into 5-amino-2-nitrobenzotrifluoride (
FLU
-1) and then further oxidized. In our previous study, N-hydroxy
FLU
-1 (
FLU
-1 N-OH) was detected in the urine of patients and exhibited cytotoxicity in rat primary hepatocytes. In the present study, we have assessed the roles of
FLU
-1 N-oxidation and hepatic glutathione (GSH) depletion in liver injury.
FLU
-1 (200 mg/kg p.o.) was administered to C57BL/6 mice for 5 days together with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) (3 mg/kg i.p.) for the first 3 days. Mice were fasted for the last 2 days to deplete hepatic GSH. Administration of
FLU
-1 alone did not affect serum alanine aminotransferase activities (ALT), whereas coadministration of
FLU
-1 and TCPOBOP significantly increased ALT in fasted mice but not in nonfasted mice. Microsomal
FLU
-1 N-hydroxylation was enhanced approximately 5 times by TCPOBOP treatment. Flutamide metabolite-protein adducts were detected in liver microsomes incubated with
FLU
-1 N-OH, but not with
FLU
-1 and flutamide, by immunoblotting using antiflutamide antiserum. In the presence of mouse liver cytosol,
FLU
-1 N-OH was reduced back into
FLU
-1. This enzymatic reduction required NAD(P)H as a cofactor. The reduction was enhanced by the coexistence of NAD(P)H and GSH, whereas it was markedly inhibited by allopurinol (20 microM). By using purified bovine
xanthine oxidase
, the reduction was observed in the presence of NAD(P)H. These results suggest that
FLU
-1 N-OH is involved in flutamide-induced hepatotoxicity and that cytosolic reduction of
FLU
-1 N-OH plays a major role in protection against flutamide-induced hepatotoxicity.
...
PMID:Role of enzymatic N-hydroxylation and reduction in flutamide metabolite-induced liver toxicity. 1883 80
