Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 481-487 |
| Number of pages | 7 |
| Journal | Mutagenesis |
| Volume | 29 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Nov 2014 |
Keywords
- DNA ADDUCT LEVELS
- HYDROCARBON HYDROXYLASE-ACTIVITY
- INDUCIBLE FACTOR
- LUNG-CANCER
- GENETIC INSTABILITY
- FACTOR 1-ALPHA
- KNOCKOUT MICE
- FACTOR-1
- BINDING
- UBIQUITYLATION
Cite this
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Hypoxia diminishes the detoxification of the environmental mutagen benzo[a]pyrene. / Schults, M.A.C.; Sanen, K.; Godschalk, R.W.; Theys, J.; van Schooten, F.J.; Chiu, R.K.
In: Mutagenesis, Vol. 29, No. 6, 11.2014, p. 481-487.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Hypoxia diminishes the detoxification of the environmental mutagen benzo[a]pyrene
AU - Schults, M.A.C.
AU - Sanen, K.
AU - Godschalk, R.W.
AU - Theys, J.
AU - van Schooten, F.J.
AU - Chiu, R.K.
PY - 2014/11
Y1 - 2014/11
N2 - Hypoxia promotes genetic instability and is therefore an important factor in carcinogenesis. We have previously shown that activation of the hypoxia responsive transcription factor HIFalpha can enhance the mutagenic phenotype induced by the environmental mutagen benzo[a]pyrene (BaP). To further elucidate the mechanism behind the ability of hypoxia to increase mutagenicity of carcinogens, we examined the activation and detoxification of BaP under hypoxic conditions. To this end, the human lung carcinoma cell line A549 was treated with BaP under 20%, 5% or 0.2% oxygen for 18h and alterations in BaP metabolism were assayed. First, BaP-induced expression of key metabolic enzymes was analysed; expression levels of the activating CYP1A1 and CYP1B1 were increased, while the detoxifying enzymes UGT1A6 and UGT2B7 were significantly reduced by hypoxia. To evaluate whether these changes had an effect on metabolism, levels of BaP and several of its metabolites were determined. Cells under hypoxia have a reduced capacity to metabolise BaP leaving more of the parent molecule intact. Additionally, BaP-7,8-dihydrodiol, the pre-cursor metabolite of the reactive metabolite BaP-7,8-dihydroxy-9,10-epoxide (BPDE), was formed in higher concentrations. Finally, under hypoxia, DNA adducts accumulated over a period of 168 h, whereas adducts were efficiently removed in 20% oxygen conditions. The delayed detoxification kinetics resulted in a 1.5-fold increase in DNA adducts. These data indicate that the metabolism under hypoxic conditions has shifted towards increased activation of BaP instead of detoxification and support the idea that modulation of carcinogen metabolism is an important additional mechanism for the observed HIF1 mediated genetic instability.
AB - Hypoxia promotes genetic instability and is therefore an important factor in carcinogenesis. We have previously shown that activation of the hypoxia responsive transcription factor HIFalpha can enhance the mutagenic phenotype induced by the environmental mutagen benzo[a]pyrene (BaP). To further elucidate the mechanism behind the ability of hypoxia to increase mutagenicity of carcinogens, we examined the activation and detoxification of BaP under hypoxic conditions. To this end, the human lung carcinoma cell line A549 was treated with BaP under 20%, 5% or 0.2% oxygen for 18h and alterations in BaP metabolism were assayed. First, BaP-induced expression of key metabolic enzymes was analysed; expression levels of the activating CYP1A1 and CYP1B1 were increased, while the detoxifying enzymes UGT1A6 and UGT2B7 were significantly reduced by hypoxia. To evaluate whether these changes had an effect on metabolism, levels of BaP and several of its metabolites were determined. Cells under hypoxia have a reduced capacity to metabolise BaP leaving more of the parent molecule intact. Additionally, BaP-7,8-dihydrodiol, the pre-cursor metabolite of the reactive metabolite BaP-7,8-dihydroxy-9,10-epoxide (BPDE), was formed in higher concentrations. Finally, under hypoxia, DNA adducts accumulated over a period of 168 h, whereas adducts were efficiently removed in 20% oxygen conditions. The delayed detoxification kinetics resulted in a 1.5-fold increase in DNA adducts. These data indicate that the metabolism under hypoxic conditions has shifted towards increased activation of BaP instead of detoxification and support the idea that modulation of carcinogen metabolism is an important additional mechanism for the observed HIF1 mediated genetic instability.
KW - DNA ADDUCT LEVELS
KW - HYDROCARBON HYDROXYLASE-ACTIVITY
KW - INDUCIBLE FACTOR
KW - LUNG-CANCER
KW - GENETIC INSTABILITY
KW - FACTOR 1-ALPHA
KW - KNOCKOUT MICE
KW - FACTOR-1
KW - BINDING
KW - UBIQUITYLATION
U2 - 10.1093/mutage/geu034
DO - 10.1093/mutage/geu034
M3 - Article
VL - 29
SP - 481
EP - 487
JO - Mutagenesis
JF - Mutagenesis
SN - 0267-8357
IS - 6
ER -