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Benzo[a]pyrene-7,8-dione (B[a]P-7,8-dione) is produced in human lung cells by the oxidation of (±)-B[a]P-7,8-trans-dihydrodiol, which is catalyzed by aldo-keto reductases (AKRs). However, information relevant to the cell-based metabolism of B[a]P-7,8-dione is lacking. We studied the metabolic fate of 2 μM 1,3-[(3)H(2)]-B[a]P-7,8-dione in human lung adenocarcinoma A549 cells, human bronchoalveolar H358 cells, and immortalized human bronchial epithelial HBEC-KT cells. In these three cell lines, 1,3-[(3)H(2)]-B[a]P-7,8-dione was rapidly consumed, and radioactivity was distributed between the organic and aqueous phase of ethyl acetate-extracted media, as well as in the cell lysate pellets. After acidification of the media, several metabolites of 1,3-[(3)H(2)]-B[a]P-7,8-dione were detected in the organic phase of the media by high performance liquid chromatography-ultraviolet-radioactivity monitoring (HPLC-UV-RAM). The structures of B[a]P-7,8-dione metabolites varied in the cell lines and were identified as B[a]P-7,8-dione conjugates with glutathione (GSH) and N-acetyl-l-cysteine (NAC), 8-O-monomethylated-catechol, catechol monosulfate, and monoglucuronide, and monohydroxylated-B[a]P-7,8-dione by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We also obtained evidence for the first time for the formation of an adenine adduct of B[a]P-7,8-dione. Among these metabolites, the identity of the GSH-B[a]P-7,8-dione and the NAC-B[a]P-7,8-dione was further validated by comparison to authentic synthesized standards. The pathways of B[a]P-7,8-dione metabolism in the three human lung cell lines are formation of GSH and NAC conjugates, reduction to the catechol followed by phase II conjugation reactions leading to its detoxification, monohydroxylation, as well as formation of the adenine adduct.

chemical research in toxicology

Metabolism and Distribution of Benzo[a]pyrene-7,8-dione (B[a]P-7,8-dione) in Human Lung Cells by Liquid Chromatography Tandem Mass Spectrometry: Detection of an Adenine B[a]P-7,8-dione Adduct