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.

• Keywords
• Benzo[a]pyrene, Cisplatin, Cytochrome P450, Ellipticine, Etoposide, Tumour suppressor p53,
• MeSH
• DNA Adducts metabolism   MeSH
• Benzo(a)pyrene pharmacokinetics   pharmacology   MeSH
• Cisplatin pharmacology   MeSH
• Cytochrome P-450 CYP1A1 biosynthesis   metabolism   MeSH
• Cytochrome P-450 CYP3A biosynthesis   metabolism   MeSH
• Ellipticines pharmacokinetics   pharmacology   MeSH
• Enzyme Induction drug effects   MeSH
• Etoposide pharmacology   MeSH
• Genes, p53 MeSH
• HCT116 Cells MeSH
• Carcinogens pharmacokinetics   pharmacology   MeSH
• Colorectal Neoplasms drug therapy   genetics   metabolism   pathology   MeSH
• Humans MeSH
• Activation, Metabolic MeSH
• Tumor Suppressor Protein p53 deficiency   genetics   metabolism   MeSH
• DNA Damage MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA Adducts MeSH
• Benzo(a)pyrene MeSH
• Cisplatin MeSH
• CYP1A1 protein, human MeSH Browser
• CYP3A4 protein, human MeSH Browser
• Cytochrome P-450 CYP1A1 MeSH
• Cytochrome P-450 CYP3A MeSH
• Ellipticines MeSH
• ellipticine MeSH Browser
• Etoposide MeSH
• Carcinogens MeSH
• Tumor Suppressor Protein p53 MeSH
• TP53 protein, human MeSH Browser