Pharmaceutical use of mouse models humanized for the xenobiotic receptor.
The regulation of hepatic cytochrome P450 (CYP) enzymes is implicated in both drug metabolism and drug-drug interactions. The CYP genes are induced by numerous xenobiotics, yet the inducibility shows clear species specificity. Recently, the rodent nuclear receptor PXR and its human homolog, SXR or hPXR, have been established as species-specific xeno-sensors that regulate CYP3A enzymes. By knocking-out the rodent gene and replacing it with the human receptor, a 'humanized' mouse model has been established. Displaying a human drug-response profile, this mouse represents a unique tool to dissect the drug-induced xenobiotic response and should aid the development of safer drugs.
Xie
Wen
W
Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Evans
Ronald M
RM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D015195:Drug Design; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D023421:Models, Animal; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000502:physiology*; D011987:Receptors, Steroid / Q000737:chemistry / Q000502:physiology*
D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating