Harman is a common compound in several foods, plants and beverages. Numerous studies have demonstrated its mutagenic, co-mutagenic and carcinogenic effects; however, the exact mechanism has not been fully identified.
Aryl hydrocarbon receptor (AhR) is a
transcription factor regulating the expression of the
carcinogen-activating
enzyme;
cytochrome P450 1A1 (
CYP1A1). In the present study, we examined the ability of
harman to induce AhR-mediated signal transduction in human and rat
hepatoma cells; HepG2 and H4IIE cells. Our results showed that
harman significantly induced
CYP1A1 mRNA in a time- and concentration-dependent manner. Similarly,
harman significantly induced
CYP1A1 at
protein and activity levels in a concentration-dependent manner. Moreover, the AhR antagonist,
resveratrol, inhibited the increase in
CYP1A1 activity by
harman. The
RNA polymerase inhibitor,
actinomycin D, completely abolished the
CYP1A1 mRNA induction by
harman, indicating a transcriptional activation. The role of AhR in
CYP1A1 induction by
harman was confirmed by using
siRNA specific for human AhR. The ability of
harman to induce
CYP1A1 was strongly correlated with its ability to stimulate AhR-dependent
luciferase activity and electrophoretic mobility shift assay. At post-transcriptional and post-translational levels,
harman did not affect the stability of
CYP1A1 at the
mRNA and the
protein levels, excluding other mechanisms participating in the obtained effects. We concluded that
harman can directly induce
CYP1A1 gene expression in an AhR-dependent manner and may represent a novel mechanism by which
harman promotes mutagenicity, co-mutagenicity and carcinogenicity.