Hypoxic inhibition of 3-methylcholanthrene-induced CYP1A1 expression is independent of HIF-1 alpha

Hypoxia-inducible factor- I alpha (HIF-1alpha) and aryl hydrocarbon receptor (AhR) both require dimerization with AhR nuclear translocator (ARNT) to initiate transcription of their respective target genes. It has been proposed that competition for ARNT results in decreased targeting of AhR to cytochrome P450 1A1 (CYP1A1) under hypoxia. We established primary cultures of HIF-1alpha null hepatocytes to examine the interaction between HIF-lalpha and AhR signaling. Gene expression of known HIF targets phosphoglycerate kinase (PGK), vascular endothelial growth factor (VEGF) and glucose transporter-I (GLUT-1) increased under hypoxia, but was reduced in the HIF null cultures. Concomitant treatment of cultures with hypoxia (I % O-2) and 3methylcholanthrene (an AhR ligand) did not significantly alter HIF target gene expression. Furthermore, enzymatic activity and transcription of CYP1A1 was inhibited by hypoxia in HIF- I a null cultures, indicating that HIF- 1alpha is not directly involved in negative regulation of AhR signaling. (C) 2004 Elsevier Ireland Ltd. All tights reserved.