title: Highly purified hexachlorobenzene induces cytochrome P4501A in primary cultures of chicken embryo hepatocytes.
abstract: Some uncertainty exists regarding the purity of hexachlorobenzene (HCB) used in past toxicity studies. It has been suggested that reported toxic and biochemical effects initially attributed to HCB exposure may have actually been elicited by contamination of HCB by polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). Herein, primary cultures of chicken embryo hepatocytes (CEH) were used to compare the potencies of two lots of reagent-grade hexachlorobenzene (HCB-old [HCB-O] and HCB-new [HCB-N]), highly purified HCB (HCB-P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as inducers of ethoxyresorufin O-deethylase (EROD) activity, cytochrome P4501A4 (CYP1A4) messenger ribonucleic acid (mRNA) and CYP1A5 mRNA. The study also compared the EROD- and CYP1A4/5 mRNA-inducing potencies of HCB to the potencies of two mono-ortho substituted polychlorinated biphenyls (PCBs), 2,3,3',4,4'-pentachlorobiphenyl (PCB 105) and 2,3'4,4',5-pentachlorobiphenyl (PCB 118). HCB-O, HCB-N and HCB-P all induced EROD activity and up-regulated CYP1A4 and CYP1A5 mRNAs. Induction was not caused by contamination of HCB with PCDDs or PCDFs. Based upon a comparison of the EC(50) and EC(threshold) values for EROD and CYP1A4/5 mRNA concentration-response curves, the potency of HCB relative to the potency of TCDD was 0.0001, and was similar to that of PCB 105 and PCB 118. The maximal EROD activity and CYP1A4/5 mRNA expression differed greatly between HCB and TCDD, and may contribute to an overestimation of the ReP value calculated for highly purified HCB.
authors.affiliation: Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Lukas J
authors.initials: LJ
authors.lastname: Mundy
authors.forename: Stephanie P
authors.initials: SP
authors.lastname: Jones
authors.forename: Doug
authors.initials: D
authors.lastname: Crump
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Hervé
authors.forename: Alex
authors.initials: A
authors.lastname: Konstantinov
authors.forename: Fiona
authors.initials: F
authors.lastname: Utley
authors.forename: David
authors.initials: D
authors.lastname: Potter
authors.forename: Sean W
authors.initials: SW
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D002478:Cells, Cultured; D002642:Chick Embryo; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination / Q000517:prevention & control; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006581:Hexachlorobenzene / Q000302:isolation & purification* / Q000633:toxicity*
chemical_list: D006581:Hexachlorobenzene; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C108015:cytochrome P-450 CYP1A5