Epidemiological evidence indicated that there was a synergistic interaction between
arsenic and cigarette
smoke on enhancement of
lung cancer risk.
Benzo[a]pyrene (B[a]P), a component in cigarette
smoke, is one of the most carcinogenic compounds known. Animal studies have demonstrated that there were increased
benzo[a]pyrene-7,8-diol-9,10-
epoxide (
BPDE) adduct formation and lung
tumorigenesis in animals when they were coexposed to B[a]P and
arsenic. Since
BPDE adduct is a by-product of B[a]P metabolism, elevation of B[a]P metabolism by
arsenic is suspected. However, the effects of
arsenic on
cytochrome P450 1A1 (
CYP1A1) status (expression and activity), which is essential for B[a]P metabolism, either in lung cells or in lung tissues, are never demonstrated. We hypothesized that
arsenic would enhance
aryl hydrocarbon receptor (AhR) activation leading to
CYP1A1 expression and activity in lung cells. Indeed, our present study successfully demonstrated the elevation of
CYP1A1 messenger RNA expression in H1355 cells, a human
lung adenocarcinoma cell line, as well as
CYP1A1 expression and activity in lung tissues of
arsenic-exposed mice. We further demonstrated that this elevation of
CYP1A1 expression could be effectively blocked with AhR antagonist,
3',4'-dimethoxyflavone, indicating that the
arsenic-induced
CYP1A1 expression and activity were via AhR activation. Furthermore, we found that
arsenic-induced AhR activation and -enhanced
CYP1A1 expression can be further increased by a prooxidant,
buthionine-(S,R)-sulfoximine, and suppressed by
antioxidants, such as
N-acetylcysteine and
catalase. Our findings provided clear evidence that
arsenic can enhance
CYP1A1 expression and activity via AhR activation, and the
arsenic-induced AhR activation is probably triggered by oxidative stress.