The metabolic N-oxidation of carcinogenic arylamines in relation to nitrogen charge density and oxidation potential.
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 Hückel 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kadlubar
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Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079.
Fu
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Jung
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Shaikh
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Beland
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D000588:Amines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008658:Inactivation, Metabolic; D009584:Nitrogen; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism; D013329:Structure-Activity Relationship
D000588:Amines; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D009584:Nitrogen