Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR).
The nuclear receptor PXR (pregnane X receptor) protects the body from hepatotoxicity of secondary bile acids such as lithocholic acid (LCA) by inducing expression of the hydroxylating cytochrome P450 enzyme CYP3A and promoting detoxification. We found that activation of PXR also increases the activity and gene expression of the phase II conjugating enzyme dehydroepiandrosterone sulfotransferase (STD) known to sulfate LCA to facilitate its elimination. This activation is direct and appears to extend to other xenobiotic sulfotransferases as well as to 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), an enzyme that generates the donor cofactor for the reaction. Because sulfation plays an important role in the metabolism of many xenobiotics, prescription drugs, and toxins, we propose that PXR serves as a master regulator of the phase I and II responses to facilitate rapid and efficient detoxification and elimination of foreign chemicals.
Sonoda
Junichiro
J
Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Xie
Wen
W
Rosenfeld
John M
JM
Barwick
Joyce L
JL
Guzelian
Philip S
PS
Evans
Ronald M
RM
D000818:Animals; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008095:Lithocholic Acid / Q000378:metabolism / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000077297:Pregnane X Receptor; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D013431:Sulfates; D015262:Xenobiotics; D008095:Lithocholic Acid; D015238:Sulfotransferases; C019998:dehydroepiandrosterone sulfotransferase