Benzamidoxime reductase

A cytochrome P450-dependent, oxygen-insensitive reducing system that catalyzes the efficient reduction of strongly basic primary N-hydroxylated functional groups such as amidines, guanidines, and amidinohydrazones was isolated from pig liver and characterized by Clement et al.226 The reconstituted system, termed benzamidoxime reductase, is composed of NADH, cytochrome b5, its reductase, phosphatidylcholine, and a cytochrome P450 from the 2D family.

In subsequent investigations this enzyme system was found to be an efficient reductant of aliphatic hydroxylamines (e.g., amphetamine hydroxylamine (208)), in liver microsomal preparations,227 mitochondria, and other organs and organelles,228 Its reducing efficiency in conjunction with the wider bio-distribution of the activity suggested its potential usefulness in a pro-drug strategy for administering strongly basic drugs. Such drugs are generally poorly adsorbed because they are virtually 100% protonated throughout the gastrointestinal tract. Administration of the less basic hydroxylamine analogs should increase adsorption, allowing the pro-drug to reach the systemic circulation, where it could be reduced to generate the parent drug.228 This approach was tried with ximelagatran (209), a pro-drug of the thrombin inhibitor melagratan (210), and was found to increase the oral bioavailability of 210 from 3-7% to 18-24% (Scheme 25).229 While the hydroxylamine was efficiently and rapidly reduced in humans, the specific cytochrome P450 that catalyzed the reaction could not be identified.230

Scheme 25

The benzamidoxime system has recently231 been found capable of reducing the N-hydroxylamines of sulfamethoxazole (211) and dapsone (82), without cytochrome P450. The notion that the reductase system between the human and pig might differ with regard to the relevance of cytochrome P450 has been proposed by Andersson etal.232 They concluded that neither cytochrome P450 nor FMO is an essential element of the reductase system in the human, based on selective inhibitors, while cytochrome b5 reductase and nonheme iron probably are.

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