Gene Expression Changes of Phases I and II Metabolizing Enzymes Induced by PAH Derivatives

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants, and generate various types of PAH derivatives, such as nitrated PAHs, hydroxylated PAHs, and PAH quinones through chemical reactions in the atmosphere. PAHs are well known to activate the aryl hydrocarbon receptor (AhR), followed by the induction of metabolizing enzymes mainly in the liver, while biological responses to PAH derivatives are not understood well. In this study, we investigated the induction patterns of gene expression of CYP1 family and Phase II metabolizing enzymes in rat H4IIE cells exposed to PAH quinones and their parent PAHs for 24 h. Dibenz[a,h]anthracene and benzo[a]pyrene dramatically induced mRNA expression of CYP1 family, such as cytochrome P450 (Cyp) 1a1, Cyp1a2, and Cyp1b1, and PAH quinones, especially 1,4-chrysenequinone, possess a high potential to induce CYP1 family. As for Phase II enzymes, PAHs induced NAD(P)H: quinone oxidoreductase 1 (Nqo1) and UDP-glucuronosyltransferase (Ugt)1a6, and their induction potencies by PAHs were similar to those of CYP1 family. On the other hand, expression of sulfotransferase (Sult)1a1, heme oxygenase-1 (Hmox1), and Ugt2b1 were augmented mainly by PAH derivatives. Finally, we examined gene expression changes of metabolizing enzymes by the airborne particles. Their organic extracts significantly up-regulated the expression of Cyp1a1, Cyp1a2, Cyp1b1, Ugt1a6, and Nqo1, but not Hmox1, Ugt2b1, and Sult1a1. These results suggest that PAHs mainly induce the expression of genes encoding CYP1 family while PAH derivatives, especially quinones, induce the expression of genes encoding both CYP1 family and Phase II enzymes. Furthermore, our results show the organic chemicals which adsorb on the airborne particles exert biological effects in the similar manner of PAHs, suggesting the involvement of mainly AhR activation.