Flavin-containing reductase: new perspective on the detoxification of nitrobenzodiazepine

Abstract

Importance of the field: Nitrobenzodiazepines (NBDZs) are important hypnotic-sedative drugs prescribed in clinic for treating sleeping disorders. The long-lasting efficacy of NBDZs has made them to be used purposely resulting in neurophysiological impairment and internal toxicity. While many studies have investigated the biotransformation of NBDZs, studies seldom are found on their reductive metabolism or the enzymes that act on these drugs.

Areas covered in this review: In this review, we describe the finding of human hepatic NADPH-cytochrome P450 reductase (EC 1.6.2.4) and Escherichia coli nitroreductase NfsB (EC 1.5.1.34) in the reductive conversion of NBDZ to a harmless metabolite 7-aminobenzodiazepine and present the facts of reductive activity in other flavin-containing reductases. A historic investigation on the reduction of nitroaromatics and quinones by the selected flavoenzymes is performed. In addition, flavin domain structures of these enzymes are discussed.

What the reader will gain: The reader will gain a comprehensive understanding of the reductive metabolism of NBDZs including the structure–activity relationship of the selected flavoproteins.

Take home message: The discovery of novel flavin-containing reductase on NBDZ in the body is essential for the development of more active nitroreductases which may find applications in the detoxification of NBDZ.

Keywords::

• Escherichia coli nitroreductase NfsB
• flavin-containing reductase
• NADPH-cytochrome P450 reductase
• nitrobenzodiazepine
• rational enzyme design

Notes

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