RT Journal Article
SR Electronic
T1 CYP3A4 Induction by Drugs: Correlation between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 795
OP 804
DO 10.1124/dmd.30.7.795
VO 30
IS 7
A1 Gang Luo
A1 Mark Cunningham
A1 Sean Kim
A1 Tim Burn
A1 Jianrong Lin
A1 Michael Sinz
A1 Geraldine Hamilton
A1 Christopher Rizzo
A1 Summer Jolley
A1 Darryl Gilbert
A1 April Downey
A1 Daniel Mudra
A1 Richard Graham
A1 Kathy Carroll
A1 Jindong Xie
A1 Ajay Madan
A1 Andrew Parkinson
A1 Dave Christ
A1 Bernard Selling
A1 Edward LeCluyse
A1 Liang-Shang Gan
YR 2002
UL http://dmd.aspetjournals.org/content/30/7/795.abstract
AB Induction of cytochrome P450 3A4 (CYP3A4) is determined typically by employing primary culture of human hepatocytes and measuring CYP3A4 mRNA, protein and microsomal activity. Recently a pregnane X receptor (PXR) reporter gene assay was established to screen CYP3A4 inducers. To evaluate results from the PXR reporter gene assay with those from the aforementioned conventional assays, 14 drugs were evaluated for their ability to induce CYP3A4 and activate PXR. Sandwiched primary cultures of human hepatocytes from six donors were used and CYP3A4 activity was assessed by measuring microsomal testosterone 6β-hydroxylase activity. Hepatic CYP3A4 mRNA and protein levels were also analyzed using branched DNA technology/Northern blotting and Western blotting, respectively. In general, PXR activation correlated with the induction potential observed in human hepatocyte cultures. Clotrimazole, phenobarbital, rifampin, and sulfinpyrazone highly activated PXR and increased CYP3A4 activity; carbamazepine, dexamethasone, dexamethasone-t-butylacetate, phenytoin, sulfadimidine, and taxol weakly activated PXR and induced CYP3A4 activity, and methotrexate and probenecid showed no marked activation in either system. Ritonavir and troleandomycin showed marked PXR activation but no increase (in the case of troleandomycin) or a significant decrease (in the case of ritonavir) in microsomal CYP3A4 activity. It is concluded that the PXR reporter gene assay is a reliable and complementary method to assess the CYP3A4 induction potential of drugs and other xenobiotics. The American Society for Pharmacology and Experimental Therapeutics