naphthoquinones and 2-tert-butyl-4-quinone

While it has long been believed that benzenes and naphthalenes are unable to activate the aryl hydrocarbon receptor (AhR) because they are poor ligands, we recently reported that these quinoid metabolites upregulated cytochrome P450 1A1 (CYP1A1) in Hepa1c1c7 cells (Abiko et al., 2015). In the current study, AhR activation, measured with a bioluminescence-based cell free assay, was induced by 1,2-naphthoquinone (1,2-NQ), a metabolite of naphthalene. Consistent with this, 1,4-benzoquinone (1,4-BQ), tert-butyl-1,4-BQ, and 1,4-NQ, as well as 1,2-NQ, all electrophilic mono- and bi-cyclic quinones, upregulated CYP1A1 mRNA and protein in HepG2 cells, whereas their parent aromatic hydrocarbons had little effect. Furthermore, immunofluorescence analysis confirmed that these quinones enhanced translocation of AhR to the nucleus.

Topics: Active Transport, Cell Nucleus; Aryl Hydrocarbon Receptor Nuclear Translocator; Basic Helix-Loop-Helix Transcription Factors; Benzoquinones; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Enzyme Induction; Fluorescent Antibody Technique; Hep G2 Cells; Hepatocytes; Humans; Naphthoquinones; Quinones; Receptors, Aryl Hydrocarbon; RNA, Messenger; Transfection

The effect of several structurally related 1,4-benzoquinones (BQ) and 1,4-naphthoquinones (NQ) on the activity of rat hepatic glutathione S-transferases (GST) was studied. For the 1,4-benzoquinones, the extent of inhibition increased with an increasing number of halogen substituents. Neither the type of halogen nor the position of chlorine-atoms was of major importance. Similarly, 2,3-dichloro-NQ demonstrated a considerably higher inhibitory activity than 5-hydroxy-NQ. 2-Methyl derivatives of NQ did not inhibit GST activity at all. The irreversible nature of the inhibition was shown both by the time-course of the inhibition as well as by the fact that removal of the inhibitor by ultrafiltration did not restore the enzymatic activity. Incubation of quinones and enzyme in the presence of the competitive inhibitor S-hexyl-glutathione, slowed the inhibition considerably, indicating an involvement of the active site. Isoenzyme 3-3 was found to be most sensitive towards the whole series of inhibitors, whereas the activity of isoenzyme 2-2 was least affected in all cases. The inhibition by quinones is probably mainly due to covalent modification of a specific cysteine residue in or near the active site. The differential sensitivities of individual isoenzymes indicates that this residue is more accessible and/or easier modified in isoenzyme 3-3 than in any of the other isoenzymes tested. The findings suggest that quinones form a class of compounds from which a selective in vivo inhibitor of the GST might be developed.

Topics: Animals; Benzoquinones; Glutathione; Glutathione Transferase; Isoenzymes; Liver; Molecular Structure; Naphthoquinones; Quinones; Rats; Structure-Activity Relationship