Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.1.1.1 (
alcohol dehydrogenase
)
9,284
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Benzo[a]pyrene (BP) requires metabolic activation to electrophiles to exert its deleterious effects. We compared the respective roles of aldo-keto reductase 1A1 (AKR1A1,
aldehyde reductase
) and
P4501B1
in the formation of BP-7,8-dione and BP-tetrols, respectively, in intact bronchoalveolar cells manipulated to express either enzyme. Metabolite formation was confirmed by HPLC/MS and quantitatively measured by HPLC/UV/beta-RAM. In TCDD-treated H358 cells (
P4501B1
expression), the anti-BPDE hydrolysis product BP-tetrol-1 increased over 3-12 h to a constant level. In H358 AKR1A1 transfectants, formation of BP-7,8-dione was elevated for 3-12 h but significantly decreased after 24 h. Interestingly, BP-tetrols were also detected in AKR1A1 transfectants even though they do not constitutively express P4501A1/
P4501B1
enzymes. Northern and Western blotting confirmed the induction of
P4501B1
by BP-7,8-dione in parental cells and the induction of
P4501B1
by BP-7,8-diol in AKR1A1-transfected cells.
P4501B1
induction was blocked in AKR1A1 transfectants by the AKR1A1 inhibitor (sulfonylnitromethane), the o-quinone scavenger (N-acetyl-l-cysteine), or the cytosolic AhR antagonist (diflubenzuron). Attenuation of
P4501B1
induction in these cells was verified by measuring a decrease in BP-tetrol formation. Our studies show that the formation of BP-7,8-dione by AKR1A1 in human bronchoalveolar cells leads to an induction of
P4501B1
and that a functional consequence of this induction is elevated anti-BPDE production as detected by increased BP-tetrol formation. Therefore, the role of AKR1A1 in the activation of BP-7,8-diol is bifunctional; that is, it directly activates BP-7,8-diol to the reactive and redox-active PAH o-quinone (BP-7,8-dione) and it indirectly trans-activates the
P4501B1
gene by generating the aryl hydrocarbon receptor (AhR) ligand BP-7,8-dione.
...
PMID:Competing roles of aldo-keto reductase 1A1 and cytochrome P4501B1 in benzo[a]pyrene-7,8-diol activation in human bronchoalveolar H358 cells: role of AKRs in P4501B1 induction. 1641 58
