![[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}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication December 7, 2005.
Revised December 23, 2005.
Accepted for publication December 23, 2005.
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, as compared to wild-type Cyp1a1(+/+) mice [Uno et al., Mol Pharmacol 2004; 65: 1225]. To further investigate the mechanism for this enhanced sensitivity, Cyp1a1(-/-), Cyp1a2(-/-) and Cyp1b1(-/-) single-knockout and Cyp1a1/1b1(-/-) and Cyp1a2/1b1(-/-) double-knockout, and Cyp1(+/+) wild-type mice were analyzed. Following 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, blood benzo[a]pyrene steady-state levels were ~25 and ~75 times higher in Cyp1a1(-/-) and Cyp1a1/1b1(-/-) mice, respectively, than 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: [a] inducible CYP1A1, probably in both intestine and liver, is most important in detoxication; [b] CYP1B1 in spleen and marrow is responsible for metabolic activation of benzo[a]pyrene, which results in immune damage in the absence of CYP1A1; [c] both thymus atrophy and hepatocyte hypertrophy are independent of CYP1B1 metabolism but rather may reflect chronic activation of the aryl hydrocarbon receptor; and [d] the magnitude of immune damage in Cyp1a1(-/-) and Cyp1a1/1b1(-/-) mice is independent of plasma benzo[a]pyrene 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.
Key words:
Regulation of gene expression, Cytochrome P450, Genetics, Ah receptor, Genetics, Reactive intermediates, Toxicant-induced gene express, Pharmacokinetics, metabolism and activation
This article has been cited by other articles:
|
|
 |
|
  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, August 18, 2008; (2008) gen041v1. [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]
|
|
 |
 |
 |
|
 |
 |
 |
