Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Kang, Ping; Dalvie, Deepak; Smith, Evan; Zhou, Sue; Deese, Alan; Nieman, James A.

doi:10.1124/dmd.108.020370

Cited by 48 publications

(49 citation statements)

References 31 publications

(38 reference statements)

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“…10). It has been reported that two GSH adducts were detected in human liver microsomal incubation of FLU-1 in the presence of NADPH and GSH (Kang et al, 2008). These results suggest the protective role of hepatic GSH in flutamideinduced liver injury.…”

Section: Figsupporting

confidence: 59%

Role of EnzymaticN-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Ohbuchi¹,

Miyata²,

Nagai³

et al. 2008

Drug Metab Dispos

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ABSTRACT: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 M). 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 flutamideinduced hepatotoxicity and that cytosolic reduction of FLU-1 N-OH plays a major role in protection against flutamide-induced hepatotoxicity.

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Section: Figsupporting

confidence: 59%

Role of EnzymaticN-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Ohbuchi¹,

Miyata²,

Nagai³

et al. 2008

Drug Metab Dispos

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“…It was identified as 2-methyl-N-[4-amino-3-(trifloromethyl)phenyl]propanamide (3) by correlation spectra together with published data. 6,8) Compound 4 (14 mg, 3.0%) was isolated as an off-white solid with a molecular formula C 9 H 9 F 3 N 2 O. The 1 H-NMR data of 4 differed from those of 3 in the absence of signals due to the isopropyl group and the presence of a methyl group instead.…”

Section: Resultsmentioning

confidence: 99%

“…3) In addition to 2-hydroxyflutamide mono-, di-and trihydroxylated flutamides have been identified. 8) The absence of the hydroxylated metabolites and the predominant presence of FLU-1 along with FLU-4 and FLU-6 in culture media suggest that the fungal metabolism of flutamide takes place exclusively via amide bond cleavage pathway (Chart 1). 3) Flutamide and its major microbial transformation product, FLU-1 are nitroaromatic compounds which undergo nitroreductive metabolism to yield FLU-6 and FLU-4 (detected in human urine).…”

Section: Resultsmentioning

confidence: 99%

“…The three metabolites isolated and characterized were detected as products in vitro and in vivo experiments as well. 3,4,[6][7][8] The major routes of flutamide metabolism in humans include P450 mediated oxidation to 2-hydroxyflutamide and cleavage of the amide bond to FLU-1. 3) In addition to 2-hydroxyflutamide mono-, di-and trihydroxylated flutamides have been identified.…”

Section: Resultsmentioning

confidence: 99%

“…6) The major metabolites detected in plasma are 2-hydroxyflutamide (OH-FLU) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) 7) with concentrations higher than that of flutamide. 8) It is suggested that the antiandrogen activity of flutamide is largely associated with its main metabolite, 2-hydroxyflutamide. 6) Its activity is based on the ability to attach itself to the receptors of the cancer cells preventing the attachment of testosterone, the male hormone which is essential for the growth of the prostate cancer cells.…”

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confidence: 99%

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Microbial Metabolism. Part 11. Metabolites of Flutamide

Herath

Khan

2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Flutamide, a nonsteroidal antiandrogen is a commonly used drug to treat advanced prostate cancer, 2) which is one of the leading causes of death in men in the United States. 3) It is absorbed rapidly from the gastrointestinal track of humans and rats after oral administration and undergoes extensive metabolism in the liver [3][4][5] through hydrolysis, hydroxylation, N-acetylation and nitroreduction to yield several metabolites. 6) The major metabolites detected in plasma are 2-hydroxyflutamide (OH-FLU) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) 7) with concentrations higher than that of flutamide. 8) It is suggested that the antiandrogen activity of flutamide is largely associated with its main metabolite, 2-hydroxyflutamide. 6) Its activity is based on the ability to attach itself to the receptors of the cancer cells preventing the attachment of testosterone, the male hormone which is essential for the growth of the prostate cancer cells. Flutamide with the structure similar to that of testosterone 9) however, is a weak antiandrogen. 10) FLU-1, which is devoid of any antiandrogenic activity 7) is formed by carboxyesterase-catalysed hydrolysis. 6) It is a product of a clearance pathway. Thus, the main metabolite identified in urine is 2-amino-5-nitro-4-(trifluoromethyl)phenol (FLU-3). 3) However, urinary excretion is not a major pathway of flutamide elimination in humans. 7) The use of flutamide as therapeutic agent against prostrate cancers is eclipsed by rare incidences of idiosyncratic liver injury. 6) Although it is suggested that flutamide and its toxic metabolites could be responsible for such hepatic injury the mechanism of toxicity remains presently unknown. 6) It is observed that the serum concentration of FLU-1 is higher 3,7) and that of OH-flutamide is lower in patients with liver dysfunction than in those with normal liver function. 11) The formation of OH-flutamide from the parent compound is catalyzed by CYP1A2. Thus, a lower concentration of OH-flutamide is due to reduced activity of the enzyme. 11) Therefore, it is suggested that since CYP1A2 seems to be involved in the initiation of flutamide-induced liver injury, attention should be paid to patients with low CYP1A2 activity before administrating flutamide. 11) Genetic mutations and factors such as smoking, food and drugs are shown to influence the activity of the enzyme. 11) Smoking induces CYP1A2 activity and reduces the risk of liver toxicity due to flutamide. 3) In the present investigation we used microbial models retrospectively in an attempt to obtain mammalian metabolites of 1. No more than three metabolites were detected in the culture media of the forty microorganisms used. Among them the most prominent compound was FLU-1, detected in almost all the cultures used. Rhodotorula mucilaginosa culture which gave all three metabolites in good yields was selected for scale up studies. The structures of the metabolites (2-4) were elucidated by detailed study of their high resolution spectroscopic data. Results and DiscussionOf the for...

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Conjugation and Transport Processes

Coleman

2010

Human Drug Metabolism

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Bioactivation of Flutamide Metabolites by Human Liver Microsomes

Cited by 48 publications

References 31 publications

Role of EnzymaticN-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Role of EnzymaticN-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity

Microbial Metabolism. Part 11. Metabolites of Flutamide

Conjugation and Transport Processes

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