Synthesis and Stability Studies of the Glutathione and N-Acetylcysteine Adducts of an Iminoquinone Reactive Intermediate Generated in the Biotransformation of 3-(N-Phenylamino)propane-1,2-diol:  Implications for Toxic Oil Syndrome

Abstract

Epidemiological studies have pointed to fatty acid mono- and diesters of 3-(N-phenylamino)propane-1,2-diol (PAP) as the biomarkers of the toxic oil batches that caused toxic oil syndrome (TOS), an intoxication episode that occurred in Spain in 1981, causing over 400 deaths and affecting more than 20000 people. The biotransformation of PAP administered intraperitoneally to two mouse strains produced potentially toxic metabolites. The identification of 3-(4'-hydroxyphenylamino)propane-1,2-diol among those metabolites was important because the compound can generate the quinoneimine intermediate 2. The potential toxicity of quinoneimines has been attributed primarily to their electrophilic character. Accordingly, the reactions of 2 with N-acetylcysteine, N-acetylcysteine methyl ester, and GSH were investigated. Quinoneimine 2 reacts with the N-acetylcysteine methyl ester to give the expected conjugate as a major product, accompanied by the corresponding bis and tris adducts. The monoadduct, when isolated in pure form, undergoes spontaneous oxidation to generate a new quinoneimine intermediate, which in turn rearranges and undergoes hydrolysis to afford the thiol adduct formally derived from the quinoneimine generated from p-aminophenol. The same overall pathway was observed for the reaction of 2 with N-acetylcysteine and GSH. Both thiol reagents reacted with the quinoneimine to give the corresponding adducts in which the addition took place at the ortho position with respect to the amino group. These conjugates were also unstable and ultimately afforded the corresponding adduct derived from p-aminophenol. The relevancy of these results to TOS, as well as their potential generalization for quinoneimines derived from other xenobiotics, is discussed herein.

Monocyclic aromatic amines as potential human carcinogens: old is new again

“…Lastly, the thioether conjugates become bound to proteins through the same Michael reaction that produces the glutathione adducts or through addition–elimination reactions in which the protein displaces one of the thioether moieties. Examples of each of these steps have been reported (46–48), including the formation of multiple glutathione adducts of aminophenol (49) as well as the aminophenol metabolite of 3-( N -phenylamino)propane-1,2-diol considered responsible for toxic oil syndrome (50). Further studies (51,52) have probed the molecular biological effects of 2,3,5- tris -(glutathion- S -yl)hydroquinone (TGHQ) as well as effects on cell signaling and mutagenesis (53–55).…”

Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species

“…Hydroquinone is a nephrotoxin and its glutathions-yl adducts exhibit multiple genetic effects (Lau et al, 2001;Patel et al, 2003;Weber et al, 2001;Yang et al, 2005;Yoon et al, 2001). Quinone imines likewise form thioether addition products with glutathione and by analogy might be expected to have similar genotoxic effects (Jefferies et al, 1998;Klos et al, 1992;Martínez-cabot et al, 2005).…”

Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

“…3−5 Aminophenol formation is not necessarily the end point of oxidative metabolism if the substitution is ortho or para : it has recently been shown that these structures may be further transformed in vivo to quinone imines. 6,7 Quinone imines are electrophiles and can undergo Michael addition with thiols and amines. They might, therefore, be capable of reacting with DNA nucleobases as a means of bringing about the mutagenic and carcinogenic effects observed with some alkylanilines such as 3,5-dimethylaniline, 8 the focus of the present work.…”