![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio
The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(-/-) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(+/+) wild-type mice. At an oral BaP dose of 125 mg/kg/day, Cyp1a1(-/-) mice died within 30 days whereas Cyp1a1(+/+) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(-/-) than Cyp1a1(+/+) mice. The cause of death in Cyp1a1(-/-) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(-/-) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(-/-) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(+/+) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.
Address correspondence to: Daniel W. Nebert, Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056. E-mail: dan.nebert{at}uc.edu
This article has been cited by other articles:
|
|
 |
|
  C. Naspinski, X. Gu, G.-D. Zhou, S. U. Mertens-Talcott, K. C. Donnelly, and Y. Tian Pregnane X Receptor Protects HepG2 Cells from BaP-Induced DNA Damage Toxicol. Sci., July 1, 2008; 104(1): 67 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Dragin, Z. Shi, R. Madan, C. L. Karp, M. A. Sartor, C. Chen, F. J. Gonzalez, and D. W. Nebert Phenotype of the Cyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse Mol. Pharmacol., June 1, 2008; 73(6): 1844 - 1856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nakayama, I. Riesen, B. Kollner, E. Eppler, and H. Segner Surface Marker-Defined Head Kidney Granulocytes and B Lymphocytes of Rainbow Trout Express Benzo[a]pyrene-Inducible Cytochrome P4501A Protein Toxicol. Sci., May 1, 2008; 103(1): 86 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Arlt, M. Stiborova, C. J. Henderson, M. Thiemann, E. Frei, D. Aimova, R. Singh, G. Gamboa da Costa, O. J. Schmitz, P. B. Farmer, et al. Metabolic activation of benzo[a]pyrene in vitro by hepatic cytochrome P450 contrasts with detoxification in vivo: experiments with hepatic cytochrome P450 reductase null mice Carcinogenesis, March 1, 2008; 29(3): 656 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. J. de Waard, T. M. C. M. de Kok, L. M. Maas, A. A. C. M. Peijnenburg, R. L. A. P. Hoogenboom, J. M. M. J. G. Aarts, and F.-J. van Schooten Influence of TCDD and natural Ah receptor agonists on benzo[a]pyrene-DNA adduct formation in the Caco-2 human colon cell line Mutagenesis, January 1, 2008; 23(1): 67 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gao, L. A. Mitchell, F. T. Lauer, and S. W. Burchiel p53 and ATM/ATR Regulate 7,12-Dimethylbenz[a]anthracene-Induced Immunosuppression Mol. Pharmacol., January 1, 2008; 73(1): 137 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schnekenburger, G. Talaska, and A. Puga Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation Mol. Cell. Biol., October 15, 2007; 27(20): 7089 - 7101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. McMillan and C. A. Bradfield The Aryl Hydrocarbon Receptor sans Xenobiotics: Endogenous Function in Genetic Model Systems Mol. Pharmacol., September 1, 2007; 72(3): 487 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Sugamori, D. Brenneman, S. Wong, A. Gaedigk, V. Yu, H. Abramovici, R. Rozmahel, and D. M. Grant Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse Drug Metab. Dispos., July 1, 2007; 35(7): 1064 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Ma and A. Y. H. Lu CYP1A Induction and Human Risk Assessment: An Evolving Tale of in Vitro and in Vivo Studies Drug Metab. Dispos., July 1, 2007; 35(7): 1009 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Sugamori, D. Brenneman, and D. M. Grant In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice Drug Metab. Dispos., October 1, 2006; 34(10): 1697 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Billiard, A. R. Timme-Laragy, D. M. Wassenberg, C. Cockman, and R. T. Di Giulio The Role of the Aryl Hydrocarbon Receptor Pathway in Mediating Synergistic Developmental Toxicity of Polycyclic Aromatic Hydrocarbons to Zebrafish Toxicol. Sci., August 1, 2006; 92(2): 526 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Ciolino, C. J. MacDonald, O. S. Memon, S. E. Bass, and G. C. Yeh Sulindac regulates the aryl hydrocarbon receptor-mediated expression of Phase 1 metabolic enzymes in vivo and in vitro Carcinogenesis, August 1, 2006; 27(8): 1586 - 1592. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Dragin, T. P. Dalton, M. L. Miller, H. G. Shertzer, and D. W. Nebert For Dioxin-induced Birth Defects, Mouse or Human CYP1A2 in Maternal Liver Protects whereas Mouse CYP1A1 and CYP1B1 Are Inconsequential J. Biol. Chem., July 7, 2006; 281(27): 18591 - 18600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Peltonen, P.-L. Lukinmaa, C. Sahlberg, A.-M. Partanen, A. Kiukkonen, and S. Alaluusua 7,12-Dimethylbenz[a]anthracene Interferes with the Development of Cultured Mouse Mandibular Molars Toxicol. Sci., July 1, 2006; 92(1): 279 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Uno, T. P. Dalton, N. Dragin, C. P. Curran, S. Derkenne, M. L. Miller, H. G. Shertzer, F. J. Gonzalez, and D. W. Nebert Oral Benzo[a]pyrene in Cyp1 Knockout Mouse Lines: CYP1A1 Important in Detoxication, CYP1B1 Metabolism Required for Immune Damage Independent of Total-Body Burden and Clearance Rate Mol. Pharmacol., April 1, 2006; 69(4): 1103 - 1114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Galoch, A Sapota, M Skrzypinska-Gawrysiak, and A Kilanowicz Acute toxicity of polychlorinated naphthalenes and their effect on cytochrome P450 Human and Experimental Toxicology, February 1, 2006; 25(2): 85 - 92. [Abstract] [PDF]
|
|
|
|
 |
|
 D. W. Nebert Comparison of gene expression in cell culture to that in the intact animal: relevance to drugs and environmental toxicants. Focus on "Development of a transactivator in hepatoma cells that allows expression of phase I, phase II, and chemical defense genes" Am J Physiol Cell Physiol, January 1, 2006; 290(1): C37 - C41. [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Hecht, M. Chen, A. Yoder, J. Jensen, D. Hatsukami, C. Le, and S. G. Carmella Longitudinal Study of Urinary Phenanthrene Metabolite Ratios: Effect of Smoking on the Diol Epoxide Pathway Cancer Epidemiol. Biomarkers Prev., December 1, 2005; 14(12): 2969 - 2974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Musafia-Jeknic, B. Mahadevan, C. Pereira, and W. M. Baird Long-Term Effects of a Standardized Complex Mixture of Urban Dust Particulate on the Metabolic Activation of Carcinogenic Polycyclic Aromatic Hydrocarbons in Human Cells in Culture Toxicol. Sci., December 1, 2005; 88(2): 358 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gao, F. T. Lauer, S. Dunaway, and S. W. Burchiel Cytochrome P450 1B1 Is Required for 7,12-Dimethylbenz(a)-anthracene (DMBA) Induced Spleen Cell Immunotoxicity Toxicol. Sci., July 1, 2005; 86(1): 68 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Georgiadis, J. Topinka, D. Vlachodimitropoulos, M. Stoikidou, M. Gioka, G. Stephanou, H. Autrup, N. A. Demopoulos, K. Katsouyanni, R. Sram, et al. Interactions between CYP1A1 polymorphisms and exposure to environmental tobacco smoke in the modulation of lymphocyte bulky DNA adducts and chromosomal aberrations Carcinogenesis, January 1, 2005; 26(1): 93 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Nebert, T. P. Dalton, A. B. Okey, and F. J. Gonzalez Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer J. Biol. Chem., June 4, 2004; 279(23): 23847 - 23850. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
