PT  - JOURNAL ARTICLE
AU  - Gang Luo
AU  - Mark Cunningham
AU  - Sean Kim
AU  - Tim Burn
AU  - Jianrong Lin
AU  - Michael Sinz
AU  - Geraldine Hamilton
AU  - Christopher Rizzo
AU  - Summer Jolley
AU  - Darryl Gilbert
AU  - April Downey
AU  - Daniel Mudra
AU  - Richard Graham
AU  - Kathy Carroll
AU  - Jindong Xie
AU  - Ajay Madan
AU  - Andrew Parkinson
AU  - Dave Christ
AU  - Bernard Selling
AU  - Edward LeCluyse
AU  - Liang-Shang Gan
TI  - CYP3A4 Induction by Drugs: Correlation between a Pregnane X Receptor Reporter Gene Assay and CYP3A4 Expression in Human Hepatocytes
AID  - 10.1124/dmd.30.7.795
DP  - 2002 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 795--804
VI  - 30
IP  - 7
4099  - http://dmd.aspetjournals.org/content/30/7/795.short
4100  - http://dmd.aspetjournals.org/content/30/7/795.full
SO  - Drug Metab Dispos2002 Jul 01; 30
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