Molecular Pharmacology, Vol 13, 185-195, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Activation of the Parasympathomimetic Alkaloid Slaframine by Microsomal and Photochemical Oxidation

¹ Department of Biochemistry and Center in Environmental Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
² Department of Biochemistry, Michigan State University, East Lansing, Michigan 48823

Slaframine (1-acetoxy-6-aminooctahydroindolizine) is photochemically converted to two major products. On the basis of chemical studies done on the NaBH₄-reduced materials, structures have been assigned. The first compound arises from deamination and rearrangement to a cyclic imine. The second compound is apparently formed by direct electron transfer and hydrolysis to produce a ketoimine. The two compounds can be separated from each other and from slaframine by ion-exchange chromatography; the latter product is biologically active while the former is not. The same products are formed with rat or porcine liver microsomes in the presence and absence of pyridine nucleotides; the microsomal activation is also insensitive to carbon monoxide, 2-diethylaminoethyl 2,2-diphenylvalerate, cyanide, and prior treatment of the animals with phenobarbital or 3-methylcholanthrene. Purified porcine hepatic microsomal flavoprotein oxidase was shown to oxidize slaframine to the active metabolite; either reduced or oxidized pyridine nucleotides enhanced product formation by stabilizing the enzyme. This enzyme appears to oxidize slaframine directly and is postulated to be primarily responsible for slaframine activation in vivo.

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ACKNOWLEDGMENT We are indebted to Dr. D. M. Ziegler for providing purified flavoprotein oxidase.