Oxidative bioactivation of nitrofurantoin in rat liver microsomes.
1. Nitrofurantoin (NFT), a 5-nitrofuran derivative, has been widely used for the treatment of specific urinary tract infections. It has been reported that exposure to NFT was associated with various adverse effects, particularly hepatotoxicity and pneumotoxicity. The objective of the study was to identify reactive metabolites of NFT and explore the mechanisms of the toxicities. 2. An epoxide intermediate generated in microsomal incubations was trapped by glutathione (GSH) and 4-bromobenzyl mercaptan (BBM), and the resulting GSH and BBM conjugates were characterized by LC-MS/MS. A spontaneous denitration took place in the trapping reaction. 2-Nitrofuran and 2-hydroxyfuran as model compounds were employed to probe the mechanism of the denitration. 3. The oxidative activation of NFT was P450-dependent, and P450 3A5 and P450 2A6 were the principal enzymes responsible for the bioactivation. The findings facilitate the understanding of the mechanisms of NFT-induced toxicities.
a School of Pharmacy.
Hui
H
Li
a School of Pharmacy.
Dongju
D
Lin
a School of Pharmacy.
Ying
Y
Peng
b Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University , Shenyang , Liaoning , China , and.|c Division of Gastroenterology and Hepatology , Department of Pediatrics, Center for Developmental Therapeutics, Seattle Children's Research Institute, University of Washington School of Medicine , Seattle , WA , USA.
Jiang
J
Zheng
D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000378:metabolism*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D009582:Nitrofurantoin / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats
D000892:Anti-Infective Agents, Urinary; D003577:Cytochrome P-450 Enzyme System; D009582:Nitrofurantoin; D005978:Glutathione
Nitrofurantoin; oxidative bioactivation; reactive metabolite