The impact of chemotherapeutic drugs on the CYP1A1-catalysed metabolism of the environmental carcinogen benzo[a]pyrene: Effects in human colorectal HCT116 TP53(+/+), TP53(+/−) and TP53(−/−) cells

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.

Impact of p53 function on the sulfotransferase‐mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1‐hydroxymethylpyrene in vitro

“…In HCT116 cells, p53-mediated induction of CYP1A1 was observed after treatment with PAHs such as BaP, DBA, and DBP (Wohak et al 2016). When studying several chemotherapeutic drugs, it was found that etoposide and ellipticine induced CYP1A1 in HCT116 TP53(+/+) cells, but not in HCT116 TP53(−/−), demonstrating that the mechanism of CYP1A1 induction was p53-dependent, whereas cisplatin had no such effects (Willis et al 2018). In the present study, 1-HMP treatment did not result in the induction of SULT1A1/3.…”

“…In addition to the role of p53 in DNA damage response, new functions are still being discovered. Over recent years, a role for p53 in modulating carcinogen metabolism has emerged Simoes et al 2008;Krais et al 2016a;Krais et al 2016b;Wohak et al 2016;Willis et al 2018;Wohak et al 2018). We have shown that DNA adduct formation by BaP was significantly impacted by p53 function both in vitro and in vivo and that the observed DNA damage correlates with CYP1A1 expression (Krais et al 2016a;Wohak et al 2016).…”

“…p53 can be induced by multiple forms of cellular stress (e.g., DNA damage) and it functions at the crossroads of a network of signaling pathways that are crucial for regulating cell growth and apoptosis. Over recent years, a role for p53 in modulating carcinogen metabolism has emerged Simoes et al 2008;Krais et al 2016a;Krais et al 2016b;Wohak et al 2016;Willis et al 2018;Wohak et al 2018). Disruption of the normal p53 response by TP53 mutation leads to the development of tumors and various carcinogens have been associated with characteristic mutational signatures (Kucab et al 2015).…”

The impact of p53 function on the metabolic activation of the carcinogenic air pollutant 3-nitrobenzanthrone and its metabolites 3-aminobenzanthrone and N-hydroxy-3-aminobenzanthrone in human cells

“…HCT116 TP53(+/+ ), TP53(+/− ), TP53(−/− ), TP53(R248W/+ ) and TP53(R248W/− ) cells were treated with 1 µM 3-NBA, 10 µM 3-ABA, 1 µM N -OH-3-ABA or DMSO alone (control) for 48 h and whole cell lysates were analysed for the expression of p53 and p21 by western blotting. Both proteins have been shown to be sensitive markers to assess DNA damage response in HCT116 cells ( 23 , 39 ). As seen in Figure 4 , treatment with 3-NBA resulted in strong induction of p53 in TP53(+/+ ), TP53(R248W/+ ) and TP53(R248W/− ) cells whereas 3-ABA and N -OH-3-ABA induced p53 to a lesser extent in these cell lines.…”

“…Thus, the lower band is assumed to be nonspecific. The antibody has been shown to be sensitive to detect human CYP1A1 protein in cultured human cells (including HCT116) exposed to BaP ( 23 , 39–41 ). However, in this study CYP1A1 protein expression after 3-NBA, 3-ABA and N -OH-ABA exposure was weak or hardly detectable ( Figure 4 ).…”