Abstract
Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) can induce cytochrome P450 1A1 (CYP1A1) via a p53-dependent mechanism. The effect of different p53-activating chemotherapeutic drugs on CYP1A1 expression, and the resultant effect on BaP metabolism, was investigated in a panel of isogenic human colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/–) or TP53(–/–) were treated for up to 48 h with 60 μM cisplatin, 50 μM etoposide or 5 μM ellipticine, each of which caused high p53 induction at moderate cytotoxicity (60–80% cell viability). We found that etoposide and ellipticine induced CYP1A1 in TP53(+/+) cells but not in TP53(–/–) cells, demonstrating that the mechanism of CYP1A1 induction is p53-dependent; cisplatin had no such effect. Co-incubation experiments with the drugs and 2.5 μM BaP showed that: (i) etoposide increased CYP1A1 expression in TP53(+/+) cells, and to a lesser extent in TP53(–/–) cells, compared to cells treated with BaP alone; (ii) ellipticine decreased CYP1A1 expression in TP53(+/+) cells in BaP co-incubations; and (iii) cisplatin did not affect BaP-mediated CYP1A1 expression. Further, whereas cisplatin and etoposide had virtually no influence on CYP1A1-catalysed BaP metabolism, ellipticine treatment strongly inhibited BaP bioactivation. Our results indicate that the underlying mechanisms whereby etoposide and ellipticine regulate CYP1A1 expression must be different and may not be linked to p53 activation alone. These results could be relevant for smokers, who are exposed to increased levels of BaP, when prescribing chemotherapeutic drugs. Beside gene-environment interactions, more considerations should be given to potential drug-environment interactions during chemotherapy.
Highlights
The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant produced from the incomplete combustion of organic material and has been classified by the International Agency for Research on Cancer as a human carcinogen (Group 1) (IARC 2010)
The effects of drugs on BaP-induced cytochrome P450 1A1 (CYP1A1) expression and on BaP metabolism We studied the effect of cisplatin, etoposide and ellipticine treatment on BaP
We found that both etoposide and ellipticine had an effect on CYP1A1 expression whereas cisplatin did not
Summary
The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant produced from the incomplete combustion of organic material and has been classified by the International Agency for Research on Cancer as a human carcinogen (Group 1) (IARC 2010). The metabolism of BaP is predominantly catalysed by cytochrome P450 (CYP) enzymes (Reed et al, 2018), predominantly CYP1A1 and CYP1B1 (Luch and Baird, 2005). This first leads to the formation of BaP-7,8-epoxide, which is quickly metabolised by microsomal epoxide hydrolase (mEH) to BaP-7,8-dihydrodiol (Figure 1) (Stiborova et al 2016; Sulc et al 2016). BaP-7,8-dihydrodiol can be further activated by CYP1A1 generating BaP-7,8dihydrodiol-9,10-epoxide (BPDE) which is capable of reacting with DNA (Arlt et al 2015; Kucab et al 2015; Stiborova et al 2016). BaP-7,8-dihydrodiol can be activated by aldo-keto reductases leading to BaP-7,8-dione which is capable of forming DNA adducts and generating oxidative damage to DNA (Penning, 2014)
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