PAH o-quinones are electrophilic and redox active products of the aldo-keto reductase (AKR) pathway of metabolic activation. When these o-quinones enter into futile redox cycles in human lung cells they generate the mutagenic lesion 8-oxo-dGuo. We have systematically compared the enzymatic (NQO1, AKR, CBR)  rates of 2-electron reduction of quinones back to the  catechol, with the ability of COMT, SULT and UGTs to form 7-O- or 8-O- catechol conjugates using benzo[a]pyrene (B[a]P)-7,8-dione as an example. In these reactions B[a]P-7,8-dione was reduced anaerobically to the catechol and then used as a substrate for the respective phase II enzyme with the required cofactor.  Conjugates were fully characterized by a combination of LC-MS/MS and NMR, and were readily detected in human lung cells. We find that enzymatic conjugation of B[a]P-7,8-catechol cannot out compete the redox-cycling reaction. The enzymes most efficient at redox-cycling were NQO1 and AKRs themselves.  These data provide an explanation as to why PAH o-quinones are deleterious and that 2-electron reduction of o-quinones by either NQO1 or AKRs may exacerbate the production of reactive oxygen species. [Supported by CA39504 and P30-ES013508 to TMP].

Interception of PAH-o-quinone redox cycling by human phase II enzymes

246th National Meeting (2013)

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