Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 31, Issue 11, Pages 1277-1288Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.chemrestox.8b00250
Keywords
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Funding
- Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Pharmacology/Toxicology Pre-Doctoral Fellowship
- National Institute of Environmental Health Sciences (NIEHS), NIH, DHHS [P30 ES013508, T32019851]
- National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Health Impact of Environmental Hazards at King's College London
- Public Health England (PHE)
- Imperial College London
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3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen detected in diesel exhaust particulate and ambient air pollution. It requires metabolic activation via nitroreduction to promote DNA adduct formation and tumorigenesis. NAD(P)H:quinone oxidoreductase 1 (NQO1) has been previously implicated as the major nitroreductase responsible for 3-NBA activation, but it has recently been reported that human aldo-keto reductase 1C3 (AKR1C3) displays nitroreductase activity toward the chemotherapeutic agent PR-104A. We sought to determine whether AKR1C isoforms could display nitroreductase activity toward other nitrated compounds and bioactivate 3-NBA. Using discontinuous enzymatic assays monitored by UV-HPLC, we determined that AKR1C1-1C3 catalyze three successive two-electron nitroreductions toward 3-NBA to form the reduced product 3-aminobenzanthrone (3-ABA). Evidence of the nitroso- and hydroxylamino- intermediates were obtained by UPLC-HRMS. K-m, k(cat), and k(cat)/K-m values were determined for recombinant AKR1C and NQO1 and compared. We found that AKR1C1, AKR1C3, and NQO1 have very similar apparent catalytic efficiencies (8 vs 7 min(-1)mM(-1)) despite the higher k(cat) of NQO1 (0.058 vs 0.012 min(-1)). AKR1C1-1C3 possess a K-m much lower than that of NQO1, which suggests that they may be more important than NQO1 at the low concentrations of 3 NBA to which humans are exposed. Given that inhalation represents the primary source of 3-NBA exposure, we chose to evaluate the relative importance of AKR1C1-1C3 and NQO1 in human lung epithelial cell lines. Our data suggest that the combined activities of AKR1C1-1C3 and NQO1 contribute equally to the reduction of 3-NBA in A549 and HBEC3-KT cell lines and together represent approximately 50% of the intracellular nitroreductase activity toward 3-NBA. These findings have significant implications for the metabolism of nitrated polycyclic aromatic hydrocarbons and suggest that the hitherto unrecognized nitroreductase activity of AKR1C enzymes should be further investigated.
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