Northern Kentucky University
Cytochrome P4501A1 and Arsenic in Benzo(A)Pyrene-Induced Carcinogenesis
Institution
Northern Kentucky University
Faculty Advisor/ Mentor
David Thompson
Abstract
The environmental pollutants arsenic and benzo(a)pyrene (BaP) are well-known human carcinogens commonly found together in substances such as cigarette smoke. Arsenic is usually addressed as a non-mutagenic co-carcinogen, with the potential to enhance the effects of mutagens such as BaP, although the mechanisms remain unclear. BaP exerts its carcinogenic effects by forming DNA adducts, leading to DNA replication errors and mutations. The detoxification of BaP in the liver is a multi-step process requiring several enzymes, notably cytochrome P4501A1 (CYP1A1). Furthermore BaP is a potent inducer of transcription of the CYP1A1 gene. Interestingly, depending upon the pathway of action by CYP1A1, BaP may undergo chemical activation into its ultimate carcinogenic metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). In this study we examined the impact of arsenic on CYP1A1 activity during BaP exposure, utilizing zebrafish (Danio rerio) as a model species. Co-exposure of zebrafish to arsenic and BaP led to decreased CYP1A1 activity when compared to BaP alone, as measured by the EROD assay. The effect is likely transcriptional, as quantitative PCR detection indicated a decrease of CYP1A1 transcript in zebrafish exposed to both arsenic and BaP when compared to BaP alone. This observed impact of arsenic on CYP1A1 activity may alter cellular levels of BPDE, thus potentially influencing BaP-induced carcinogenesis.
Cytochrome P4501A1 and Arsenic in Benzo(A)Pyrene-Induced Carcinogenesis
The environmental pollutants arsenic and benzo(a)pyrene (BaP) are well-known human carcinogens commonly found together in substances such as cigarette smoke. Arsenic is usually addressed as a non-mutagenic co-carcinogen, with the potential to enhance the effects of mutagens such as BaP, although the mechanisms remain unclear. BaP exerts its carcinogenic effects by forming DNA adducts, leading to DNA replication errors and mutations. The detoxification of BaP in the liver is a multi-step process requiring several enzymes, notably cytochrome P4501A1 (CYP1A1). Furthermore BaP is a potent inducer of transcription of the CYP1A1 gene. Interestingly, depending upon the pathway of action by CYP1A1, BaP may undergo chemical activation into its ultimate carcinogenic metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). In this study we examined the impact of arsenic on CYP1A1 activity during BaP exposure, utilizing zebrafish (Danio rerio) as a model species. Co-exposure of zebrafish to arsenic and BaP led to decreased CYP1A1 activity when compared to BaP alone, as measured by the EROD assay. The effect is likely transcriptional, as quantitative PCR detection indicated a decrease of CYP1A1 transcript in zebrafish exposed to both arsenic and BaP when compared to BaP alone. This observed impact of arsenic on CYP1A1 activity may alter cellular levels of BPDE, thus potentially influencing BaP-induced carcinogenesis.