Pharmacological Reviews, Vol 25, 1-66, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

Biochemical Formation and Pharmacological, Toxicological, and Pathological Properties of Hydroxylamines and Hydroxamic Acids

¹ National Cancer Institute, Bethesda, Maryland 20014

In the past most metabolic reactions on exogenous materials were considered to be detoxification reactions. However, during investigations on adverse effects of aromatic amines and related materials, it was discovered in the last 15 years that certain of these chemicals have pronounced effects on the hematopoietic system, are carcinogenic, or have other pharmacological or pathological properties because of a novel toxication reaction. This reaction consists in substituting one hydrogen on the amine nitrogen with a hydroxyl group, N-hydroxylation. N-Hydroxylation has been studied extensively both in vivo and in vitro. N-Hydroxy compounds can be produced by a number of methods. Chemically, selective reduction of the corresponding nitro compounds under conditions where the hydroxylamine can be isolated is generally most useful. Similarly, nitroaryl compounds can serve as substrates for an in vivo or in vitro biochemical reduction in mammalian as well as in bacterial systems.

Biochemically N-hydroxy compounds are generally the product of specific N-hydroxylation reactions on the corresponding aromatic amines. In a few instances aliphatic amines were so studied, but relatively little success was achieved in demonstrating N-hydroxylation except by indirect criteria.

Biochemical N-hydroxylation is subject to a number of limitations. With aryl amines N-hydroxylation generally proceeds better when there are no substituents ortho to the amino group. Many speciea including man have varying capability to perform N-hydroxylation, but the guines pig and the steppe lemming have the least capability. Furthermore, although many tissues can N-hydroxylate in vitro, the liver usually excels in this respect. In many but not all instances chronic administration of an arylamine yields increasing levels of an N-hydroxy derivative. In some cases this increase hss been attributed to the higher production of N-hydroxy compounds by damaged tissue such as liver. Although there are relatively minor effects due to sex, endocrine-modified animals do sometimes exhibit different capacities for N-hydroxylation.

N-Hydroxylation appears to be performed by membrane-bound ensymes on the endoplasmic reticulum just as are other types of biochemical hydroxylations. However, more information is needed on certain differences between Cand N-hydroxylation. Carbon monoxide and other selective inhibitors have less effect on N-hydmxylation than on some types of C-hydroxylation. Thus, it is not yet established that the now classic cytochrome P-450 system is involved in all types of N-hydroxylation reactions.

As with other hydroxylated derivatives, N-hydroxy compounds are good substrates for further conjugation reactions with glucuronic or sulfuric acid. Thus, N-hydroxy compounds are transported in vivo and are excreted into urine chiefly as glucuronic acid conjugates, which probably are detoxification forms. On the other hand, there is evidence that sulfate ester formation yields unstable activated metabolites which are reactive entities. These compounds can be mutagenic, carcinogenic, and highly toxic. Other esters like O-acetates are similarly endowed. However, the effect on the hematopoietic system appeara to be mediated by arylhydroxylamines reacting directly with select constituents of this system or acting as catalysts in transferring oxygen to form methemoglobin.

Thus, N-hydroxylation is a key reaction accounting for many of the phsrmacological, pathological, and other adverse effects of aromatic nitro compounds, aromatic amines, and their derivatives.

Note:

Acknowledgments. The secretarid assistance of Mrs. Nancy Branoh, Miss Flodella Mitchell, Mrs. Anna Parker, Miss Diane Weisburger, and Mrs. Frances Williams is gratefully acknowledged.

This article has been cited by other articles:

				J.-D. Duan, A. M. Jeffrey, and G. M. Williams Assessment of the Medicines Lidocaine, Prilocaine, and Their Metabolites, 2,6-Dimethylaniline and 2-Methylaniline, for DNA Adduct Formation in Rat Tissues Drug Metab. Dispos., August 1, 2008; 36(8): 1470 - 1475. [Abstract] [Full Text] [PDF]

				G. Lower Jr, T Nilsson, C. Nelson, H Wolf, T. Gamsky, and G. Bryan N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark Int. J. Epidemiol., February 1, 2007; 36(1): 11 - 18. [Full Text] [PDF]

				H. Zhou, Z. Tong, and J. F. McLeod "Cocktail" Approaches and Strategies in Drug Development: Valuable Tool or Flawed Science? J. Clin. Pharmacol., February 1, 2004; 44(2): 120 - 134. [Abstract] [Full Text] [PDF]

				S. Kitamura, K. Takekawa, K. Sugihara, K. Tatsumi, and S. Ohta Pseudoenzymatic reduction of N-hydroxy-2-acetylaminofluorene to 2-acetylaminofluorene mediated by cytochrome P450 Carcinogenesis, February 1, 1999; 20(2): 347 - 350. [Abstract] [Full Text] [PDF]

				L. D. Lehman-McKeeman, D. R. Johnson, D. Caudill, and S. B. Stuard Mechanism-Based Inactivation of Mouse Hepatic Cytochrome P4502B Enzymes by Amine Metabolites of Musk Xylene Drug Metab. Dispos., March 1, 1997; 25(3): 384 - 389. [Abstract] [Full Text]