title: In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabolically activated by isoforms of the P450 enzyme superfamily producing benzo[a]pyrene-7,8-dihydrodiol (B[a]P diol), dibenzo[def,p]chrysene-11,12 diol (DBC diol). Each of these diols can be further metabolized by cytochrome P450 enzymes to highly reactive diol-epoxide metabolites that readily react with DNA or by phase II conjugation facilitating excretion. To complement prior in vitro metabolism studies with parent B[a]P and DBC, both phase I metabolism and phase II glucuronidation of B[a]P diol and DBC diol were measured in hepatic microsomes from female B6129SF1/J mice, male Sprague-Dawley rats, and female humans. Metabolic parameters, including intrinsic clearance and Michaelis-Menten kinetics were calculated from substrate depletion data. Mice and rats demonstrated similar B[a]P diol phase I metabolic rates. Compared to rodents, human phase I metabolism of B[a]P diol demonstrated lower overall metabolic capacity, lower intrinsic clearance at higher substrate concentrations (>0.14μM), and higher intrinsic clearance at lower substrate concentrations (<0.07μM). Rates of DBC diol metabolism did not saturate in mice or humans and were highest overall in mice. Higher affinity constants and lower capacities were observed for DBC diol glucuronidation compared to B[a]P diol glucuronidation; however, intrinsic clearance values for these compounds were consistent within each species. Kinetic parameters reported here will be used to extend physiologically based pharmacokinetic (PBPK) models to include the disposition of B[a]P and DBC metabolites in animal models and humans to support future human health risk assessments.
authors.affiliation: Pacific Northwest National Laboratory, Richland, WA 99352, USA. Electronic address: jordan.smith@pnnl.gov.
authors.forename: Jordan N
authors.initials: JN
authors.lastname: Smith
authors.affiliation: Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Mehinagic
authors.affiliation: Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Nag
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Crowell
authors.affiliation: Pacific Northwest National Laboratory, Richland, WA 99352, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Corley
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D002911:Chrysenes / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: D002273:Carcinogens; D002911:Chrysenes; D004101:Dihydroxydihydrobenzopyrenes; D011084:Polycyclic Aromatic Hydrocarbons; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System
keywords: Benzo[a]pyrene; Dibenzo[def,p]chrysene; PAH; Polycyclic aromatic hydrocarbons