Investigation of the presence in human urine of mercapturic acids derived from phenanthrene, a representative polycyclic aromatic hydrocarbon

Abstract

Polycyclic aromatic hydrocarbons (PAH) are environmental carcinogens implicated as causes of cancer in certain industrial settings and in cigarette smokers. PAH require metabolic activation to exert their carcinogenic effects. One widely accepted pathway of metabolic activation proceeds through formation of “bay region” diol epoxides which are highly reactive with DNA and can cause mutations. Phenanthrene (Phe) is the simplest PAH with a bay region and an excellent model for the study of PAH metabolism. In previous studies in which [D10]Phe was administered to smokers, we observed higher levels of [D10]Phe-tetraols derived from [D10]Phe-diol epoxides in subjects who were null for the glutathione-S-transferase M1 (GSTM1) gene. We hypothesized that Phe-epoxides, the primary metabolites of Phe, were detoxified by glutathione conjugate formation, which would result ultimately in the excretion of the corresponding mercapturic acids in urine. We synthesized the four stereoisomeric mercapturic acids that would result from attack of glutathione on Phe-epoxides followed by normal processing of the conjugates. We also synthesized the corresponding dehydrated metabolites and sulfoxides. These 12 standards were used in liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry analysis of urine samples from smokers and creosote workers, the latter exposed to unusually high levels of PAH. Only the sulfoxide derivatives were consistently detected in the urine of creosote workers; none of the compounds was detected in the urine of smokers. These results demonstrate a new pathway of PAH-mercapturic acid formation, but do not provide an explanation for the role of GSTM1 null status on Phe-tetraol formation.

Exposure of Polycyclic Aromatic Hydrocarbons (PAHs) and Crude Oil to Atlantic Haddock (Melanogrammus aeglefinus): A Unique Snapshot of the Mercapturic Acid Pathway

“…MA s have also been identified as urinary metabolites in humans . Contrary to the findings of Ayala et al, MA s have been characterized as minor metabolites in cigarette smokers . However, that study measured only one out of the four potential conjugates in the MAP .…”

“…However, no indication of other functional groups was observed in the mass spectra of this compound. A proposed explanation is the elimination of water, leaving the GSH residue singly on the ring. , This observation, where only the MAP conjugate was observed on the PAH, occurred in 13 of the 33 compounds identified in our library.…”

“…51 Contrary to the findings of Ayala et al, 16 MAs have been characterized as minor metabolites in cigarette smokers. 35 However, that study measured only one out of the four potential conjugates in the MAP. Similarly, Willet et al 49 observed a minimal presence of GSH metabolites in fish bile after exposure to benzo[a]pyrene.…”

The Method and Study of Detecting Phenanthrene in Seawater Based on a Carbon Nanotube–Chitosan Oligosaccharide Modified Electrode Immunosensor

“…According to the "Bay Region Theory", a spatially hindered region is formed between c-4 and c-5 of the phenanthrene structure [6], which makes it easy for phenanthrene to enter an organism and participate in its metabolism. It is easy for phenanthrene to form bay area diol epoxide and combine with DNA, RNA, and protein, resulting in genotoxicity, gene mutation, and carcinogenesis [7,8], and it has an impact on the heart [9], blood [10], and reproductive system [11] of organisms. Considering the impact of phenanthrene on the environment and biology, the World Health Organization listed phenanthrene as a category 3 carcinogen in 2017.…”