Article

Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract.

Department of Environmental Health, and The Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Free Radical Biology and Medicine (impact factor: 5.42). 03/2008; 44(4):570-83. DOI:10.1016/j.freeradbiomed.2007.10.044
Source: PubMed

ABSTRACT The CYP1A1, CYP1A2, and CYP1B1 enzymes are inducible by benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); metabolism of BaP by these enzymes leads to electrophilic intermediates and genotoxicity. Throughout the gastrointestinal (GI) tract, we systematically compared basal and inducible levels of the CYP1 mRNAs by Q-PCR, and localized the CYP1 proteins by immunohistochemistry. Cyp1(+/+) wild-type were compared with the Cyp1a1(-/-), Cyp1a2(-/-), and Cyp1b1(-/-) single-knockout and Cyp1a1/1b1(-/-) and Cyp1a2/1b1(-/-) double-knockout mice. Oral BaP was compared with intraperitoneal TCDD. In general, maximal CYP1A1 mRNA levels were 3-10 times greater than CYP1B1, which were 3-10 times greater than CYP1A2 mRNA levels. Highest inducible concentrations of CYP1A1 and CYP1A2 occurred in proximal small intestine, whereas the highest basal and inducible levels of CYP1B1 mRNA occurred in esophagus, forestomach, and glandular stomach. Ablation of either Cyp1a2 or Cyp1b1 gene resulted in a compensatory increase in CYP1A1 mRNA - but only in small intestine. Also in small intestine, although BaP- and TCDD-mediated CYP1A1 inductions were roughly equivalent, oral BaP-mediated CYP1A2 mRNA induction was approximately 40-fold greater than TCDD-mediated CYP1A2 induction. CYP1B1 induction by TCDD in Cyp1(+/+) and Cyp1a2(-/-) mice was 4-5 times higher than that by BaP; however, in Cyp1a1(-/-) animals CYP1B1 induction by TCDD or BaP was approximately equivalent. CYP1A1 and CYP1A2 proteins were generally localized nearer to the lumen than CYP1B1 proteins, in both squamous and glandular epithelial cells. These GI tract data suggest that the inducible CYP1A1 enzyme, both in concentration and in location, might act as a "shield" in detoxifying oral BaP and, hence, protecting the animal.

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Keywords

3-10 times greater
 
CYP1 mRNAs
 
CYP1A1 mRNA
 
CYP1A2 mRNA levels
 
CYP1B1 enzymes
 
Cyp1b1 gene
 
CYP1B1 mRNA
 
detoxifying oral BaP
 
electrophilic intermediates
 
GI tract data
 
glandular stomach
 
Highest inducible concentrations
 
inducible CYP1A1 enzyme
 
inducible levels
 
maximal CYP1A1 mRNA levels
 
Oral BaP
 
oral BaP-mediated CYP1A2 mRNA induction
 
proximal small intestine
 
TCDD-mediated CYP1A1 inductions
 
TCDD-mediated CYP1A2 induction