Repression of intestinal drug metabolizing enzymes by the SV40 large T antigen.
Toxic compounds such as carcinogens are removed from the body by the action of a series of detoxifying enzymes and transporters expressed in the liver and the small intestine. We have found that intestinal epithelial cells expressing the SV40 large T antigen (TAg) contain significantly lower levels of mRNAs, encoding several drug metabolizing/detoxifying enzymes and transporters compared to their non-transgenic littermates. In addition, TAg blocks the induction of these mRNAs by xenobiotics. The repression depends on an intact LXCXE motif in TAg, suggesting that inactivation of the retinoblastoma (Rb) family of tumor suppressors plays a role in the process. These results imply that a functional Rb pathway in the intestine is necessary for the expression of the detoxification system used to clear carcinogens, and suggest that loss of this tumor suppressor might alter susceptibility to chemical injury. In addition, the effect of TAg on the detoxification pathway appears to be tissue-specific, as its ectopic expression in the liver failed to suppress the P450 enzymes. The TAg-mediated suppression of drug metabolizing/detoxifying enzymes may have broad implications in the metabolism and mechanism of action of both carcinogens and prescription drugs.
Sáenz-Robles
M T
MT
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Toma
D
D
Cantalupo
P
P
Zhou
J
J
Gong
H
H
Edwards
C
C
Pipas
J M
JM
Xie
W
W
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D013539:Simian virus 40; D015262:Xenobiotics / Q000037:antagonists & inhibitors / Q000633:toxicity
D000952:Antigens, Polyomavirus Transforming; D008565:Membrane Proteins; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A