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

The tumor suppressor p53, encoded by TP53, is known as the 'guardian of the genome'. Sulfotransferases (SULTs) are involved in the metabolism of alkylated polycyclic aromatic hydrocarbons such 1-hydroxymethylpyrene (1-HMP) which is a known substrate for SULT1A1. To investigate the impact of TP53 on the metabolic activation of 1-HMP a panel of isogenic human colorectal HCT116 cells having TP53(+/+), TP53(+/-) or TP53(-/-) were treated with 10 μM 1-HMP for 24 hours. 1-HMP-DNA adduct formation was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, which quantified two nucleoside adducts N2 -(1-methylpyrenyl)-2'-deoxyguanosine (MPdG) and N6 -(1-methylpyrenyl)-2'-deoxyadenosine (MPdA). 1-HMP treatment resulted in significantly (~40-fold) higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. Higher levels of 1-HMP-induced DNA adducts in TP53(+/+) cells correlated with higher basal expression of SULT1A1/3 in this cell line but 1-HMP treatment showed no effect on the expression of this protein. These results indicate that the cellular TP53 status is linked to the SULT1A1/3-mediated bioactivation of 1-HMP thereby broadening the spectrum of p53's targets. This article is protected by copyright. All rights reserved.