PMID: 8937860Nov 1, 1996Paper

Formation of a metabolic intermediate complex of cytochrome P4502B1 by clorgyline

Drug Metabolism and Disposition : the Biological Fate of Chemicals
U SharmaPaul F Hollenberg

Abstract

The monoamine oxidase inhibitor clorgyline was found to inactivate purified reconstituted cytochrome P450 (P450) 2B1 in a time- and concentration-dependent manner (Sharma et al., Drug Metab. Dispos. 24, 669-675, 1996). In an attempt to explain the mechanism of inactivation, the possibility of the formation of a metabolic intermediate (MI) complex during the metabolism of clorgyline by P4502B1 was investigated. Incubation with clorgyline resulted in an absorbance peak with a maximum at 455 nm in the difference spectrum that is characteristic of an MI complex, and the magnitude of absorbance at 455 nm was dependent on both the concentration of clorgyline and NADPH. The MI complex was relatively stable and did not dissociate on standing or on removal of excess inactivator by a series of dilutions followed by microconcentration. When formed using limiting amounts of NADPH, the MI complex could be dissociated by the addition of 50 microM potassium ferricyanide. Clorgyline did not inactivate the 7-ethoxycoumarin O-deethylase activity of liver microsomes from beta-naphthoflavone-treated rats or the hydroxylation of p-nitrophenol by liver microsomes from pyridine-treated rats. However, low levels of MI complex formation were observed w...Continue Reading

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