Pharmacological Reviews, Vol 21, 325-355, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

THE PHARMACOLOGY AND BIOCHEMISTRY OF N-OXIDES

¹ Medizinisch-chemisches Institut, University of Berne, Berne, Switzerland

N-Oxides are oxidation products of tertiary amines. They were detected as a new class of chemical compounds before 1900 and were later found to occur as constituents of living matter. In recent years an increasing number of studies by biomedical scientists has been devoted to N-oxides for several reasons. The natural occurrence of N-oxides in plant and animal tissues has posed interesting problems as to the biochemistry and function of these compounds in biological systems. In several cases N-oxides are more active than their corresponding tertiary amines. Hence several N-oxides are important as pharmacological or toxicological agents, e.g., in the groups of alkaloids, chemotherapeutics, antibiotics, psychotropic drugs, methemoglobin forming compounds, and carcinogenic agents. Certain oncogenic N-oxides act as antimetabolites and have been postulated as inducers of spontaneous cancer. Finally, a large number of tertiary amine drugs produce N-oxides as metabolites or intermediates in drug metabolism.

N-Oxides have been detected in animals, plants, and microorganisms. TrimethylamineN-oxide, which occurs primarily in marine species but also in mammals, including man, has received most attention; however, its biosynthesis and its physiological functions have not yet been fully elucidated. In addition to the pharmacologically active N-oxides of natural origin, many others have been prepared synthetically.

Many findings suggest that N-oxides play an important role in the metabolism of drugs. In addition to N-oxidation of tertiary amines, N-dealkylation of N-oxides has been detected. This suggested a pathway of oxidative N-dealkylation of tertiary amines in which N-oxides would be intermediate metabolites. On the other hand strong evidence for a direct tertiary amine N-dealkylation has also been presented; in this case N-oxides would be by-products. However, N-oxides could also be intermediate metabolites because of the frequently occurring N-oxide reduction which transforms them into the corresponding tertiary amines. With some substrates several or all of these four reactions have been observed to occur simultaneously. Despite many investigations carried out in an attempt to elucidate the mechanisms and enzymatic characteristics of these reactions, our knowledge is stifi incomplete.

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