title: Up-regulation of CYP1A1 and phase II enzymes by 5-ring isomeric polycyclic aromatic hydrocarbons in precision-cut rat hepatic slices: Importance of molecular shape.
abstract: The objectives of the present study were two-fold: (a) to evaluate the role of molecular shape on the interaction of polycyclic aromatic hydrocarbons (PAHs) with the Ah receptor and CYP1A1 upregulation, and (b) to evaluate the potential of PAHs to induce epoxide hydrolase and glutathione S-transferase, two major enzymes involved in their metabolism. In order to achieve these objectives, precision-cut rat liver slices were incubated with a range of concentrations of seven 5-ring isomeric PAHs, namely benzo[c]chrysene, benzo[b]chrysene, benzo[g]chrysene, dibenzo[a,j]anthracene, dibenzo[a,c]anthracene, picene and pentacene, for 24h. All compounds, with the exception of pentacene, elevated the O-deethylation of ethoxyresorufin, an activity associated with CYP1A1; induction of this enzyme by the various PAHs correlated with their avidity for the Ah receptor. None of the PAHs studied increased epoxide hydrolase activity, monitored using benzo[a]pyrene 4,5-oxide. Of the seven PAHs, only benzo[g]chrysene elevated glutathione S-transferase activity, measured using 1-chloro-2,4-dinitrobenzene or 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole as substrates. No relationship could be established between length or length/width and interaction with the Ah receptor and CYP1A1 up-regulation indicating that other structural or electronic factors are likely to be more important. Finally, 5-ring PAHs are poor inducers of the epoxide hydrolase and glutathione S-transferase enzyme systems.
authors.affiliation: Molecular Toxicology Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
authors.forename: Daphnee
authors.initials: D
authors.lastname: Pushparajah
authors.affiliation: Molecular Toxicology Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
authors.forename: Dfv
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Molecular Toxicology Group, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. Electronic address: c.ioannides@surrey.ac.uk.
authors.forename: Costas
authors.initials: C
authors.lastname: Ioannides
mesh_terms: D000818:Animals; D003198:Computer Simulation; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry* / Q000494:pharmacology*; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase
keywords: Ah receptor; CYP1; Cytochrome P450; Molecular shape; Polycyclic aromatic hydrocarbons