The metabolic N-oxidation of carcinogenic arylamines in relation to nitrogen charge density and oxidation potential

Abstract

The N-oxidation of carcinogenic arylamines to form N-hydroxy arylamines has long been regarded as a necessary metabolic step for conversion to proximate carcinogenic derivatives. In contrast, arylamine ring-oxidation has been generally considered to be an important detoxification mechanism. Both enzymatic reactions are carried out in the liver and usually involve the cytochrome P-450 monooxygenases. Studies on the metabolic oxidation of certain arylamines have indicated that the relative charge density on nitrogen versus ring-carbon atoms for a nitrenium/carbenium ion-enzyme intermediate correlates with the relative proportion of N-versus ring-hydroxylated products that are formed. A further examination of this approach now shows that positive charge density on the nitrogen, as estimated by Huckel molecular orbital calculations, is consistent with the formation of N-hydroxy arylamines from aniline, 4-aminoazobenzene, 2-naphthylamine, 4-aminobiphenyl, 2-aminofluorene, and 6-aminochrysene, but not from 1-naphthylamine, 1-aminopyrene, 6-aminobenzo[a]pyrene, or 7-aminobenz[a]anthracene. Since greater positive charge on the arylamine nitrogen implies a greater charge localization during the transition state of the enzyme-substrate complex, we envisioned that higher oxidation potentials for arylamines, which might be expected to correlate inversely with the ease of total oxidation, would instead be predictive of the relative extent of N-oxidation. When the half-wave oxidation potentials (E 1/2 's) of the above-mentioned arylamines, along with those of 1-amino-6-nitropyrene and 1-amino-8-nitropyrene (which also undergo N-oxidation but are not amenable to simple Huckel calculations), were experimentally determined by linear sweep voltammetry, an E 1/2 of greater than +0.60 V was found to be generally predictive of the ability of these arylamines to undergo metabolic N-oxidation. Thus, these methods may be applicable to other arylamines whose extent of N-oxidation and carcinogenic potential are unknown.