In contrast to hepatocytes, there is only limited information about the expression and activities of
enzymes participating in metabolic activation of environmental
mutagens, including
polycyclic aromatic hydrocarbons (PAHs), in liver progenitor cells. In rat liver "stem-like" WB-F344 cell line, sharing many characteristics with rat liver progenitor cells, PAHs are efficiently activated to their ultimate genotoxic metabolites forming
DNA adducts. The present study aimed to characterize expression/activities of
enzymes of two major pathways involved in the metabolism of
benzo[a]pyrene (BaP):
cytochrome P450 (CYP) family 1
enzymes and cytosolic
aldo-keto reductases (AKRs). We report here that, apart from induction of
CYP1A1 and CYP1B1 expression and the corresponding enzymatic activity, both BaP and
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) induced rat 3alpha-hydroxysteroid
dehydrogenase (
AKR1C9) expression and activity. In contrast, the
aldehyde reductase AKR1A1 was not induced by either treatment. Thus, both CYP1 and AKR metabolic pathways were inducible in the model of liver progenitor cells. BaP and
TCDD were efficient inducers of
NAD(P)H:
quinone oxidoreductase 1 (NQO1) expression and activity in WB-F344 cells, a principal
enzyme of cellular
antioxidant defense. Both compounds also induced expression of
transcription factor NRF2, involved in control of
enzymes protecting cells from oxidative stress. However, although BaP induced a significant formation of
reactive oxygen species, it did not induce expression of
heme oxygenase-1, suggesting that induction of oxidative stress by BaP was limited. Using
shRNA against the
aryl hydrocarbon receptor (AhR), we found that similar to
CYP1A1 and CYP1B1, the
AKR1C9 induction was AhR-dependent. Moreover, constitutive
AKR1C9 levels in AhR-deficient rat BP8
hepatoma cells were significantly lower than in their AhR-positive 5L variant, thus supporting possible role of AhR in regulation of
AKR1C9 expression. Taken together, both CYP1 and
AKR1C9 appear to be AhR-regulated metabolic pathways, which may contribute to formation of pro-carcinogenic PAH metabolites in liver progenitor cells.