Molecular Pharmacology, Vol 10, 975-985, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

The Formation of a 455 nm Complex during Cytochrome P-450-Dependent N-Hydroxyamphetamine Metabolism

¹ Departments of Pharmacology and Biopharmaceutical Sciences, University of Utah, Salt Lake City, Utah 84112

The formation of an absorbance maximum at 455 nm during the hepatic microsomal oxidative metabolism of N-hydroxyamphetamine requires NADPH and oxygen and is not inhibited by exogenous catalase. This 455 nm complex, which is thought to be a complex of a metabolic intermediate formed during N-hydroxyamphetamine metabolism by cytochrome P-450, has an extinction coefficient of 65 mM^-1 cm^-1. It can be formed at a rate 8 nmoles/ mg of protein per minute, which is 10 times the rate of formation of a similar complex from norbenzphetamine, 20 times that from benzphetamine, and 40 times that from d-amphetamine and SKF 525-A. Prior treatment of rats with phenobarbital enhances the rate of complex formation, whereas 3-methylcholanthrene administration reduces the rate to less than that observed for untreated animals. Formation of the complex is inhibited by other substrates capable of undergoing mixed-function oxidation. The complex is stable in the pressence of dithionite, but is destroyed by ferricyanide oxidation and subsequent further reduction. The 455 nm absorbance maximum is converted to one at 423 nm upon conversion of cytochrome P-450 to P-420 by deoxycholate.

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