![[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 (CEG), University of Cincinnati Medical Center, Cincinnati Ohio (T.P.D., N.D., C.P.C., S.D., M.L.M., H.G.S., D.W.N.); Department of Biochemistry, Nihon University School of Medicine, Tokyo, Japan (S.U.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
Abstract
CYP1A1 and CYP1B1 metabolically activate many polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene, to reactive intermediates associated with toxicity, mutagenesis, and carcinogenesis. Paradoxically, however, Cyp1a1-/- knockout mice are more sensitive to oral benzo[a]pyrene exposure, compared with wild-type Cyp1a1+/+ mice (Mol Pharmacol 65:1225, 2004). To further investigate the mechanism for this enhanced sensitivity, Cyp1a1-/-, Cyp1a2-/-, and Cyp1b1-/- single-knockout, Cyp1a1/1b1-/- and Cyp1a2/1b1-/- double-knockout, and Cyp1+/+ wild-type mice were analyzed. After administration of oral benzo[a]pyrene (125 mg/kg/day) for 18 days, Cyp1a1-/- mice showed marked wasting, immunosuppression, and bone marrow hypocellularity, whereas the other five genotypes did not. After 5 days of feeding, steady-state blood levels of benzo[a]pyrene were 
25 and 75 times higher in Cyp1a1-/- and Cyp1a1/1b1-/- mice, respectively, than in wild-type mice. Benzo[a]pyrene-DNA adduct levels were highest in liver, spleen, and marrow of Cyp1a1-/- and Cyp1a1/1b1-/- mice. Many lines of convergent data obtained with oral benzo[a]pyrene dosing suggest that: 1) inducible CYP1A1, probably in both intestine and liver, is most important in detoxication; 2) CYP1B1 in spleen and marrow is responsible for metabolic activation of benzo[a]pyrene, which results in immune damage in the absence of CYP1A1; 3) both thymus atrophy and hepatocyte hypertrophy are independent of CYP1B1 metabolism but rather may reflect long-term activation of the aryl hydrocarbon receptor; and 4) the magnitude of immune damage in Cyp1a1-/- and Cyp1a1/1b1-/- mice is independent of plasma benzo[a]pyrene and total-body burden and clearance. Thus, a balance between tissue-specific expression of the CYP1A1 and CYP1B1 enzymes governs sensitivity of benzo[a]pyrene toxicity and, possibly, carcinogenicity.
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:
|
|
 |
|
  D. Hughes, J. B. Guttenplan, C. B. Marcus, K. Subbaramaiah, and A. J. Dannenberg Heat Shock Protein 90 Inhibitors Suppress Aryl Hydrocarbon Receptor-Mediated Activation of CYP1A1 and CYP1B1 Transcription and DNA Adduct Formation Cancer Prevention Research, November 1, 2008; 1(6): 485 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. C. M. Staal, D. S. Pushparajah, M. H. M. van Herwijnen, R. W. H. Gottschalk, L. M. Maas, C. Ioannides, F. J. van Schooten, and J. H. M. van Delft Interactions between polycyclic aromatic hydrocarbons in binary mixtures: Effects on gene expression and DNA adduct formation in precision-cut rat liver slices Mutagenesis, November 1, 2008; 23(6): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
T. M. Penning and C. Lerman Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment Cancer Prevention Research, July 1, 2008; 1(2): 80 - 83. [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]
|
|
|
|
|
|
Y. C.M. Staal, D. G.A.J. Hebels, M. H.M. van Herwijnen, R. W.H. Gottschalk, F. J. van Schooten, and J. H.M. van Delft Binary PAH mixtures cause additive or antagonistic effects on gene expression but synergistic effects on DNA adduct formation Carcinogenesis, December 1, 2007; 28(12): 2632 - 2640. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
J. Gao, F. T. Lauer, L. A. Mitchell, and S. W. Burchiel Microsomal Expoxide Hydrolase Is Required for 7,12-Dimethylbenz[a]anthracene (DMBA)-Induced Immunotoxicity in Mice Toxicol. Sci., July 1, 2007; 98(1): 137 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Inaba, K. Yamamoto, N. Yoshimoto, M. Matsunawa, S. Uno, S. Yamada, and M. Makishima Vitamin D3 Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators Mol. Pharmacol., May 1, 2007; 71(5): 1298 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. N. Operana, N. Nguyen, S. Chen, D. Beaton, and R. H. Tukey Human CYP1A1GFP Expression in Transgenic Mice Serves as a Biomarker for Environmental Toxicant Exposure Toxicol. Sci., January 1, 2007; 95(1): 98 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. C.M. Staal, M. H.M. van Herwijnen, D. S. Pushparajah, M. Umachandran, C. Ioannides, F. J. van Schooten, and J. H.M. van Delft Modulation of gene expression and DNA-adduct formation in precision-cut liver slices exposed to polycyclic aromatic hydrocarbons of different carcinogenic potency Mutagenesis, January 1, 2007; 22(1): 55 - 62. [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]
|
|
|
|
 |
|
 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]
|
|
 |
 |
 |
|
 |
 |
 |
