Epidemiological studies provided strong indications that there was interaction between cigarette smoke and arsenic in the elevation of lung cancer risk among cigarette smoker in arseniasis areas. Animal studies also demonstrated an increased BaP-DNA adducts in lung tissues from animals co-exposed to BaP and arsenic. BaP is a cigarette smoke component and a known potent carcinogen, such enhancement of its carcinogenicity in lungs may be explained by enhancements of its metabolic activation (metabolites and DNA-adduct formation) in the presence of arsenic. We have investigated the influences of arsenic on the P450 CYP1A1 and CYP1B1 enzymes which were the primary metabolizing enzymes for BaP. We found that arsenic increased the CYP1A1, but not CYP1B1, mRNA expression in lung cells both in vitro and in vivo. When the CYP1 enzyme activity was measure, we found that The CYP1 enzyme activity was, as observed by other laboratories, decreased in vitro in the presence of arsenic. However, this enzyme activity was elevated in vivo as reflected by the up-regulation of Cyp1a1 mRNA expression. This opposing findings between in vitro and in vivo observations appeared to be paradoxical. Heme oxygenase 1 (HO-1) was known to degrade the CYP1 enzyme post-translationally. Indeed, our investigation further demonstrated that the HO-1 expression was up-regulated in vitro, but not in vivo, in the presence of arsenic. Our finding provided important scientific evidence which can explain the apparent paradoxical observations on a suppressed CYP1 activity by arsenic in in vitro studies and yet an enhanced BaP metabolism and BaP-DNA adducts in animals co-exposed to BaP and arsenic.
Date:
2007-10
Relation:
Drug Metabolism Reviews. 2007 Oct;39(Suppl. 1):209.
