Enhanced Acetaminophen Toxicity by Activation of the Pregnane X Receptor Export

@article{citeulike:4689301, abstract = {The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16{alpha}-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation. 10.1093/toxsci/kfh286}, author = {Guo, Grace L. and Moffit, Jeff S. and Nicol, Christopher J. and Ward, Jerrold M. and Aleksunes, Lauren A. and Slitt, Angela L. and Kliewer, Steven A. and Manautou, Jose E. and Gonzalez, Frank J.}, citeulike-article-id = {4689301}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/toxsci/kfh286}, citeulike-linkout-1 = {http://toxsci.oxfordjournals.org/cgi/content/abstract/82/2/374}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/15456926}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=15456926}, day = {1}, doi = {10.1093/toxsci/kfh286}, journal = {Toxicol. Sci.}, keywords = {acetaminophen, sulfate\_conjugation}, month = {December}, number = {2}, pages = {374--380}, posted-at = {2009-05-31 13:51:56}, priority = {3}, title = {Enhanced Acetaminophen Toxicity by Activation of the Pregnane X Receptor}, url = {http://dx.doi.org/10.1093/toxsci/kfh286}, volume = {82}, year = {2004} }

TY - JOUR ID - citeulike:4689301 L3 - citeulike-article-id:4689301 N2 - The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16{alpha}-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation. 10.1093/toxsci/kfh286 IS - 2 JF - Toxicol. Sci. EP - 380 TI - Enhanced Acetaminophen Toxicity by Activation of the Pregnane X Receptor VL - 82 SP - 374 KW - acetaminophen KW - sulfate_conjugation AU - Guo, Grace AU - Moffit, Jeff AU - Nicol, Christopher AU - Ward, Jerrold AU - Aleksunes, Lauren AU - Slitt, Angela AU - Kliewer, Steven AU - Manautou, Jose AU - Gonzalez, Frank PY - 2004/12/01/ UR - http://dx.doi.org/10.1093/toxsci/kfh286 ER -