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Induction and inhibition of human cytochrome P4501 by oxygenated polycyclic aromatic hydrocarbons.

ABSTRACT: Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are found in the environment together with PAHs. However, less is known concerning their biological activity including their impact on aryl hydrocarbon receptor (AHR) signalling and the subsequent modulation of the cytochrome P450 monooxygenases (CYP). In this study, the effects of 15 environmentally relevant oxy-PAHs on the induction and activity of the CYP1 enzymes were determined in vitro by measuring gene expression levels and enzyme activity. We found that nine of the tested oxy-PAHs significantly induced CYP1A1 and CYP1B1 gene expression in human keratinocytes (HaCaT cells) while only five of these also were potent inducers of CYP1-dependent ethoxyresorufin-O-deethylase (EROD) activity suggesting that some of the oxy-PAHs are both activators of AHR signalling and inhibitors of CYP1 function. Using a recombinant human CYP1A1 enzyme we showed that eleven of the oxy-PAHs potently inhibited enzyme activity with benz[a]anthracene-7,12-quinone (7,12-BAQ) and benzo[a]fluorenone (BFLO) being the most potent inhibitors (IC50 = 0.037 and 0.061 ?M, respectively). We further exposed HaCaT cells to binary mixtures of oxy-PAHs and the model AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to investigate potential interaction effects. The results showed that oxy-PAHs can interfere with the TCDD-mediated effects leading to reduced CYP1A1 and 1B1 expression and EROD activity. These data represent the first demonstration that oxy-PAHs can be potent inhibitors of CYP1 expression and function and make important contributions towards understanding the mechanisms through which oxy-PAHs can contribute to the overall risk of polycyclic aromatic compounds.

SUBMITTER: Wincent E

PROVIDER: S-EPMC6062249 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Induction and inhibition of human cytochrome P4501 by oxygenated polycyclic aromatic hydrocarbons.

Wincent Emma E Le Bihanic Florane F Dreij Kristian K

Toxicology research 20160304 3

Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are found in the environment together with PAHs. However, less is known concerning their biological activity including their impact on aryl hydrocarbon receptor (AHR) signalling and the subsequent modulation of the cytochrome P450 monooxygenases (CYP). In this study, the effects of 15 environmentally relevant oxy-PAHs on the induction and activity of the CYP1 enzymes were determined <i>in vitro</i> by measuring gene expression levels and enz ...[more]

PMID: 30090389

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Project description:Eleven polycyclic aromatic hydrocarbons (PAHs) and 14 acetylenic PAHs and biphenyls were used to analyze interactions with cytochrome P450 (P450) 1B1 in inhibiting catalytic activity, using 7-ethoxyresorufin O-deethylation (EROD) as a model reaction. Most of the chemicals examined were direct inhibitors of P450 1B1 except for 4-(1-propynyl)biphenyl, a mechanism-based inhibitor. In the case of direct inhibition of EROD activity {15 of 24 chemicals, e.g., benzo[a]pyrene, 1-(1-propynyl)pyrene, and 3-(1-propynyl)phenanthrene}, restoration of the EROD activity occurred with increasing incubation time, and kinetic analysis showed that EROD K(m) values were higher with these inhibitors at initial stages of incubation but became lower with increasing incubation time. With the other nine chemicals, the K(m) values for P450 1B1-mediated EROD increased during the incubations. Acetylenic inhibitors, but not the 11 PAHs, induced reverse type I spectral changes with P450 1B1, and the low dissociation constants (K(s)) suggested a role for such interaction in the inhibition of catalytic activity. Studies of quenching of P450 1B1-derived fluorescence with inhibitors demonstrated that acetylenic inhibitors and PAHs interacted rapidly with P450 1B1, with K(d) values < 10 microM. However, studies of quenching of inhibitor-derived fluorescence with P450 1B1 showed these interactions to be different, that is, B[a]P interacted with P450 1B1 more slowly. Molecular docking of P450 1B1, based on P450 1A2 crystal structure, suggested that there are clear differences in the interaction of PAH inhibitors with P450 1B1 and 1A2 and that these differences may explain why PAH inhibitors inhibit P450 1 enzymes by different mechanisms. The results suggest that P450 1B1 interacts with synthetic polycyclic aromatic acetylenes and PAHs in different ways, depending on the chemicals, and that these differences in interactions may explain how these chemicals inhibit P450 activities by different mechanisms.

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Induction and inhibition of human cytochrome P4501 by oxygenated polycyclic aromatic hydrocarbons.

Publications

Induction and inhibition of human cytochrome P4501 by oxygenated polycyclic aromatic hydrocarbons.

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