Reductase-mediated metabolism of motexafin gadolinium (Xcytrin®) in rat and human liver subcellular fractions and purified enzyme preparations
✍ Scribed by Chitra Mani; Shubhra Upadhyay; Steve Lacy; Garry W. Boswell; Dale R. Miles
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 191 KB
- Volume
- 94
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
The biotransformation of motexafin gadolinium (MGd, Xcytrin 1 ) was investigated in subcellular rat and human liver fractions. Microsomal MGd metabolism was dependent on NADPH in both species. Cytosolic metabolism in rat and human livers was dependent on NADPH or NADH. Under anaerobic conditions, MGd metabolism increased in liver microsomes and purified enzyme preparations. Cytochrome P450 (CYP450) inhibitors ketoconazole, proadifen, and carbon monoxide increased NADPHdependent MGd metabolism in microsomes. Treatment of rats with b-naphthoflavone increased cytosolic metabolism of MGd twofold, but had no effect on microsomal metabolism. Conversely, in liver preparations from phenobarbital treated rats microsomal metabolism of MGd was enhanced twofold, but not in cytosolic preparations. Purified CYP450 reductase from phenobarbital-treated rabbit or untreated human livers metabolized MGd suggesting involvement of CYP450 reductase. Dicumarol, a potent DT-diaphorase inhibitor, inhibited MGd metabolism in both rat and human liver cytosol. These data suggest MGd metabolism in rat liver involves CYP450 reductase and/or DT-diaphorase. In human liver preparations only CYP450 reductase is directly involved in MGd metabolism. A metabolite identified in microsomes and cytosol is a metal-free, reduced form of MGd, indicating that both enzymes generate metabolite 1, which appears to be PCI-0108, a synthetic precursor to MGd.