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

  title={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},
  author={Shigeyuki Uno and Timothy P. Dalton and Nadine Dragin and Christine Perdan Curran and Sandrine Derkenne and Marian L Miller and Howard G. Shertzer and Frank J. Gonzalez and Daniel W. Nebert},
  journal={Molecular Pharmacology},
  pages={1103 - 1114}
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… 
Polycyclic Aromatic Hydrocarbon (PAH)-Induced Pulmonary Carcinogenesis in Cytochrome P450 (CYP) 1A1- and 1A2-null Mice: Roles of CYP1A1 and CYP1A2.
The hypothesis that mice lacking the genes for Cyp 1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis is tested and the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer is supported.
Vitamin D Receptor Activation Enhances Benzo[a]pyrene Metabolism via CYP1A1 Expression in Macrophages
The cross-talk between AHR and VDR signaling pathways was investigated and it was found that 1α,25-dihydroxyvitamin D3, a potent physiological VDR agonist, enhanced BaP-induced transcription of CYP1A1 in human monocytic U937 cells and THP-1 cells, breast cancer cells, and kidney epithelium-derived cells.
Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract.
Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice.
  • S. Uno, D. Nebert, M. Makishima
  • Biology, Medicine
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
  • 2018
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.
Hepatic CYP enzymes appear to be more important for detoxification of BaP in vivo, despite being involved in its metabolic activation in vitro, revealing an apparent paradox.
Inhibition of aryl hydrocarbon receptor transactivation and DNA adduct formation by CYP1 isoform-selective metabolic deactivation of benzo[a]pyrene.


Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation.
The present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.
Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas.
  • J. Buters, S. Sakai, F. Gonzalez
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
CYP1B1-null mice, created by targeted gene disruption in embryonic stem cells, were born at the expected frequency from heterozygous matings with no observable phenotype, thus establishing that
Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria.
Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism.
  • H. Liang, H. Li, D. Nebert
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
Cytochrome P450 1A2 (CYP1A2) is a predominantly hepatic enzyme known to be important in the metabolism of numerous foreign chemicals of pharmacologic, toxicologic, and carcinogenic significance.
Rat CYP1B1: an adrenal cytochrome P450 that exhibits sex-dependent expression in livers and kidneys of TCDD-treated animals.
The induction of CYP1B1 in TCDD rat liver may be a contributing factor to the carcinogenic action of this persistent environmental pollutant.
Characterization of mouse small intestinal cytochrome P450 expression.
Intestinal P450 expression was compared between C57BL/6 and 129/sv mice, strains commonly used in the preparation of transgenic and knockout mouse models, and there was no significant strain difference in constitutive levels or induction patterns for CYP2B, 2C, and 3A protein.
Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009.
There were good correlations between activities of procarcinogen activation by CYP1A1 preparations expressed in E. coli and T. ni cells, and the resultant DNA damage caused by the reactive metabolites was detected by measuring expression of umu gene in the cells.
Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery.
It is postulate that CYP1A1 and CYp1A2 might have overlapping substrate specificity for metabolism of the EL, such that basal CYP 1A2 in the liver can compensate for the loss of CYP2A1.