PMID- 36693016
OWN - NLM
STAT- MEDLINE
DCOM- 20230224
LR  - 20240221
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 36
IP  - 2
DP  - 2023 Feb 20
TI  - Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 
      2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung 
      Cells.
PG  - 270-280
LID - 10.1021/acs.chemrestox.2c00337 [doi]
AB  - 1-Nitropyrene (1-NP) is a constituent of diesel exhaust and classified as a group 
      2A probable human carcinogen. The metabolic activation of 1-NP by nitroreduction 
      generates electrophiles that can covalently bind DNA to form mutations to 
      contribute to cancer causation. NADPH-dependent P450 oxidoreductase (POR), 
      xanthine oxidase (XO), aldehyde oxidase (AOX), and NAD(P)H/quinone oxidoreductase 
      1 (NQO1) may catalyze 1-NP nitroreduction. We recently found that human 
      recombinant aldo-keto reductases (AKRs) 1C1-1C3 catalyze 1-NP nitroreduction. 
      NQO1 and AKR1C1-1C3 are genes induced by nuclear factor erythroid 2-related 
      factor 2 (NRF2). Despite this knowledge, the relative importance of these enzymes 
      and NRF2 to 1-NP nitroreduction is unknown. We used a combination of 
      pharmacological and genetic approaches to assess the relative importance of these 
      enzymes and NRF2 in the aerobic nitroreduction of 1-NP in human bronchial 
      epithelial cells, A549 and HBEC3-KT. 1-NP nitroreduction was assessed by the 
      measurement of 1-aminopyrene (1-AP), the six-electron reduced metabolite of 1-NP, 
      based on its intrinsic fluorescence properties (lambda(ex) and lambda(em)). We found that 
      co-treatment of 1-NP with salicylic acid, an AKR1C1 inhibitor, or 
      ursodeoxycholate, an AKR1C2 inhibitor, for 48 h decreased 1-AP production 
      relative to 1-NP treatment alone (control) in both cell lines. R-Sulforaphane or 
      1-(2-cyano-3,12,28-trioxooleana-1,9(11)-dien-28-yl)-1H-imidazole (CDDO-Im), two 
      NRF2 activators, each increased 1-AP production relative to control only in 
      HBEC3-KT cells, which have inducible NRF2. Inhibitors of POR, NQO1, and XO failed 
      to modify 1-AP production relative to control in both cell lines. Importantly, 
      A549 wild-type cells with constitutively active NRF2 produced more 1-AP than A549 
      cells with heterozygous expression of NFE2L2/NRF2, which were able to produce 
      more 1-AP than A549 cells with homozygous knockout of NFE2L2/NRF2. Together, 
      these data show dependence of 1-NP metabolic activation on AKR1Cs and NRF2 in 
      human lung cells. This is the second example whereby NFE2L2/NRF2 is implicated in 
      the carcinogenicity of diesel exhaust constituents.
FAU - Su, Anthony L
AU  - Su AL
AUID- ORCID: 0000-0002-5280-6423
AD  - Department of Systems Pharmacology and Translational Therapeutics, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 
      United States.
FAU - Penning, Trevor M
AU  - Penning TM
AUID- ORCID: 0000-0002-3937-1066
AD  - Department of Systems Pharmacology and Translational Therapeutics, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, 
      United States.
AD  - Center of Excellence in Environmental Toxicology, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
LA  - eng
GR  - P30 ES013508/ES/NIEHS NIH HHS/United States
GR  - R01 ES029294/ES/NIEHS NIH HHS/United States
GR  - T32 ES019851/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230124
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - TD1665I8Q4 (1-nitropyrene)
RN  - EC 1.1.1.- (Aldo-Keto Reductases)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Vehicle Emissions)
RN  - 0 (NFE2L2 protein, human)
SB  - IM
MH  - Humans
MH  - Activation, Metabolic
MH  - Aldo-Keto Reductases/metabolism
MH  - Lung/metabolism
MH  - *NF-E2-Related Factor 2/genetics/metabolism
MH  - *Vehicle Emissions
PMC - PMC9974908
MID - NIHMS1871388
COIS- Conflict of Interest TMP is a member of the Expert Panel for the Research 
      Institute for Fragrance Materials, the founder of Penzymes, and is a consultant 
      for Propella Therapeutics.
EDAT- 2023/01/25 06:00
MHDA- 2023/02/25 06:00
PMCR- 2024/02/20
CRDT- 2023/01/24 13:12
PHST- 2023/01/25 06:00 [pubmed]
PHST- 2023/02/25 06:00 [medline]
PHST- 2023/01/24 13:12 [entrez]
PHST- 2024/02/20 00:00 [pmc-release]
AID - 10.1021/acs.chemrestox.2c00337 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2023 Feb 20;36(2):270-280. doi: 10.1021/acs.chemrestox.2c00337. 
      Epub 2023 Jan 24.